Adv. Pharmacol. [JOURNAL]
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200 papers
Epigenetic and epitranscriptomic mechanisms of chromium carcinogenesis.
Wang Z, Yang C
Adv Pharmacol · 2023 · PMID 36858774 · Full text
Hexavalent chromium [Cr(VI)], a Group I carcinogen classified by the International Agency for Research on Cancer (IARC), represents one of the most common occupational and environmental pollutants. The findings from huma...
Hexavalent chromium [Cr(VI)], a Group I carcinogen classified by the International Agency for Research on Cancer (IARC), represents one of the most common occupational and environmental pollutants. The findings from human epidemiological and laboratory animal studies show that long-term exposure to Cr(VI) causes lung cancer and other cancer. Although Cr(VI) is a well-recognized carcinogen, the mechanism of Cr(VI) carcinogenesis has not been well understood. Due to the fact that Cr(VI) undergoes a series of metabolic reductions once entering cells to generate reactive Cr metabolites and reactive oxygen species (ROS) causing genotoxicity, Cr(VI) is generally considered as a genotoxic carcinogen. However, more and more studies have demonstrated that acute or chronic Cr(VI) exposure also causes epigenetic dysregulations including changing DNA methylation, histone posttranslational modifications and regulatory non-coding RNA (microRNA and long non-coding RNA) expressions. Moreover, emerging evidence shows that Cr(VI) exposure is also capable of altering cellular epitranscriptome. Given the increasingly recognized importance of epigenetic and epitranscriptomic dysregulations in cancer initiation and progression, it is believed that Cr(VI) exposure-caused epigenetic and epitranscriptomic changes could play important roles in Cr(VI) carcinogenesis. The goal of this chapter is to review the epigenetic and epitranscriptomic effects of Cr(VI) exposure and discuss their roles in Cr(VI) carcinogenesis. Better understanding the mechanism of Cr(VI) carcinogenesis may identify new molecular targets for more efficient prevention and treatment of cancer resulting from Cr(VI) exposure.
miRNAs and arsenic-induced carcinogenesis.
Nail AN, Ferragut Cardoso AP, Montero LK … +1 more , States JC
Adv Pharmacol · 2023 · PMID 36858773 · Full text
Arsenic-induced carcinogenesis is a worldwide health problem. Identifying the molecular mechanisms responsible for the induction of arsenic-induced cancers is important for developing treatment strategies. MicroRNA (miRN...
Arsenic-induced carcinogenesis is a worldwide health problem. Identifying the molecular mechanisms responsible for the induction of arsenic-induced cancers is important for developing treatment strategies. MicroRNA (miRNA) dysregulation is known to affect development and progression of human cancer. Several studies have identified an association between altered miRNA expression in cancers from individuals chronically exposed to arsenic and in cell models for arsenic-induced carcinogenesis. This chapter provides a comprehensive review for miRNA dysregulation in arsenic-induced cancer.
Arsenic and cancer: Evidence and mechanisms.
Speer RM, Zhou X, Volk LB … +2 more , Liu KJ, Hudson LG
Adv Pharmacol · 2023 · PMID 36858772 · Full text
Arsenic is a potent carcinogen and poses a significant health concern worldwide. Exposure occurs through ingestion of drinking water and contaminated foods and through inhalation due to pollution. Epidemiological evidenc...
Arsenic is a potent carcinogen and poses a significant health concern worldwide. Exposure occurs through ingestion of drinking water and contaminated foods and through inhalation due to pollution. Epidemiological evidence shows arsenic induces cancers of the skin, lung, liver, and bladder among other tissues. While studies in animal and cell culture models support arsenic as a carcinogen, the mechanisms of arsenic carcinogenesis are not fully understood. Arsenic carcinogenesis is a complex process due its ability to be metabolized and because of the many cellular pathways it targets in the cell. Arsenic metabolism and the multiple forms of arsenic play distinct roles in its toxicity and contribute differently to carcinogenic endpoints, and thus must be considered. Arsenic generates reactive oxygen species increasing oxidative stress and damaging DNA and other macromolecules. Concurrently, arsenic inhibits DNA repair, modifies epigenetic regulation of gene expression, and targets protein function due its ability to replace zinc in select proteins. While these mechanisms contribute to arsenic carcinogenesis, there remain significant gaps in understanding the complex nature of arsenic cancers. In the future improving models available for arsenic cancer research and the use of arsenic induced human tumors will bridge some of these gaps in understanding arsenic driven cancers.
Tungsten toxicity and carcinogenesis.
Bolt AM
Adv Pharmacol · 2023 · PMID 36858771 · Full text
Tungsten is an emerging contaminant in the environment. Research has demonstrated that humans are exposed to high levels of tungsten in certain settings, primarily due to increased use of tungsten in industrial applicati...
Tungsten is an emerging contaminant in the environment. Research has demonstrated that humans are exposed to high levels of tungsten in certain settings, primarily due to increased use of tungsten in industrial applications. However, our understanding of the potential human health risks of tungsten exposure is still limited. An important point we have learned about the toxicity profile of tungsten is that it is complex because tungsten can often augment the effects of other co-exposures or co-stressors, which could result in greater toxicity or more severe disease. This has shaped the tungsten toxicology field and the types of research questions being investigated. This has particularly been true when evaluating the toxicity profile of tungsten metal alloys in combination with cobalt. In this chapter, the current state of the tungsten toxicology field will be discussed focusing on data investigating tungsten carcinogenicity and other major toxicities including pulmonary, cardiometabolic, bone, and immune endpoints, either alone or in combination with other metals. Environmental and human monitoring data will also be discussed to highlight human populations most at risk of exposure to high concentrations of tungsten, the forms of tungsten present in each setting, and exposure levels in each population.
Mechanisms of chromate carcinogenesis by chromatin alterations.
Zablon HA, VonHandorf A, Puga A
Adv Pharmacol · 2023 · PMID 36858770 · Publisher ↗
In a dynamic environment, organisms must constantly mount an adaptive response to new environmental conditions in order to survive. Novel patterns of gene expression, driven by attendant changes in chromatin architecture...
In a dynamic environment, organisms must constantly mount an adaptive response to new environmental conditions in order to survive. Novel patterns of gene expression, driven by attendant changes in chromatin architecture, aid in adaptation and survival. Critical mechanisms in the control of gene transcription govern new spatiotemporal chromatin-chromatin interactions that make regulatory DNA elements accessible to the transcription factors that control the response. Consequently, agents that disrupt chromatin structure are likely to have a direct impact on the transcriptional programs of cells and organisms and to drive alterations in fundamental physiological processes. In this regard, hexavalent chromium (Cr(VI)) is of special interest because it interacts directly with cellular proteins, DNA, and other macromolecules, and is likely to upset cell functions that may cause generalized damage to the organism. Here, we will highlight chromium-mediated mechanisms that disrupt chromatin architecture and discuss how these mechanisms are integral to its carcinogenic properties. Emerging evidence indicates that Cr(VI) targets euchromatin, particularly in genomic locations flanking the binding sites of the essential transcription factors CTCF and AP1, and, in so doing, they disrupt nucleosomal architecture. Ultimately, the ensuing changes, if occurring in critical regulatory domains, may establish a new chromatin state, either toxic or adaptive, that will be governed by the corresponding gene transcription changes in key biological processes associated with that state.
Preface.
Yamazaki H
Adv Pharmacol · 2022 · PMID 35953165 · Publisher ↗
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Cytochrome P450 enzymes and metabolism of drugs and neurotoxins within the mammalian brain.
Stocco MR, Tyndale RF
Adv Pharmacol · 2022 · PMID 35953164 · Publisher ↗
Cytochrome P450 enzymes (CYPs) that metabolize xenobiotics are expressed and active in the brain. These CYPs contribute to the metabolism of many centrally acting compounds, including clinically used drugs, drugs of abus...
Cytochrome P450 enzymes (CYPs) that metabolize xenobiotics are expressed and active in the brain. These CYPs contribute to the metabolism of many centrally acting compounds, including clinically used drugs, drugs of abuse, and neurotoxins. Although CYP levels are lower in the brain than in the liver, they may influence central substrate and metabolite concentrations, which could alter resulting centrally-mediated responses to these compounds. Additionally, xenobiotic metabolizing CYPs are highly variable due to genetic polymorphisms and regulation by endogenous and xenobiotic molecules. In the brain, these CYPs are sensitive to xenobiotic induction. As a result, CYPs in the brain vary widely, including among humans, and this CYP variation may influence central metabolism and resulting response to centrally acting compounds. It has been demonstrated, using experimental manipulation of CYP activity in vivo selectively within the brain, that CYP metabolism in the brain alters central substrate and metabolite concentrations, as well as drug response and neurotoxic effects. This suggests that variability in xenobiotic metabolizing CYPs in the human brain may meaningfully contribute to individual differences in response to, and effects of, centrally acting drugs and neurotoxins. This chapter will provide an overview of CYP expression in the brain, endogenous- and xenobiotic-mediated CYP regulation, and the functional impact of CYP-mediated metabolism of drugs and neurotoxins in the brain, with a focus on experimental approaches in mice, rats, and non-human primates, and a discussion regarding the potential role of xenobiotic metabolizing CYPs in the human brain.
Pharmacogenetics of the cytochromes P450: Selected pharmacological and toxicological aspects.
Daly AK
Adv Pharmacol · 2022 · PMID 35953163 · Publisher ↗
With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across...
With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail. Bleeding due to warfarin and other coumarin anticoagulants is considered as an example of a type A reaction with idiosyncratic adverse drug reactions affecting the liver and skin as type B. It is clear that CYP2C9 variants contribute significantly to warfarin dose requirement and also risk of bleeding, with a minor contribution from CYP4F2. In the case of idiosyncratic adverse drug reactions, CYP2B6 variants appear relevant to both liver and skin reactions to several drugs with CYP2C9 variants also relevant to phenytoin-related skin rash. The relevance of P450 genotype to disease susceptibility is also considered but detailed genetic studies now suggest that CYP2A6 is the only P450 relevant to risk of lung cancer with alleles associated with low or absent activity clearly protective against disease. Other cytochrome P450 genotypes are generally not predictors for risk of cancer or other complex disease development.
Cytochrome P450 polymorphism: From evolution to clinical use.
Ingelman-Sundberg M
Adv Pharmacol · 2022 · PMID 35953162 · Publisher ↗
The cytochromes P450s can be divided in two groups, those of high importance for endogenous functions being evolutionary quite stable and those participating in detoxification of drugs and other xenobiotics having less i...
The cytochromes P450s can be divided in two groups, those of high importance for endogenous functions being evolutionary quite stable and those participating in detoxification of drugs and other xenobiotics having less important endogenous functions. In the latter group extensive genetic diversity has been allowed and in addition this is of high importance for survival in different environments. The genetic polymorphisms in these genes have evolved to some extent based on dietary restrictions and environmental factors and have not been subject of conservation due to less importance for survival. In cases of high dietary selection events, gene multiplication and amplification events have been seen. The different variants in genes encoding drug metabolizing enzymes can be used as genetic biomarkers (pharmacogenomic labels) for adjustment of drug treatment leading to less adverse drug reactions and better response. Indeed, this has improved the use of personalized medicine, although the missing heredity seen based on twin studies indicates that there are indeed many more genetic variants to be discovered before one can achieve a satisfactory relationship between genotype and phenotype with respect to drug metabolism and toxicity.
Cytochrome P450 enzymes in the pediatric population: Connecting knowledge on P450 expression with pediatric pharmacokinetics.
Emoto C, Johnson TN
Adv Pharmacol · 2022 · PMID 35953161 · Publisher ↗
Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by...
Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by deconvolution of in vivo pharmacokinetic data observed in pediatric populations. The age-dependent changes in P450 enzyme expression can be important determinants of drug disposition in childhood, in addition to the changes in body size and the other physiological parameters, and effects of pharmacogenetics and disease on organ functions. As a tool incorporating drug-specific and body-specific factors, physiologically-based pharmacokinetic (PBPK) models have become increasingly used to characterize and explore mechanistic insights into drug disposition. Thus, PBPK models can be a bridge between findings from basic science and utilization in predictive science. Pediatric PBPK models incorporate additional system specific information on developmental physiology and ontogeny and have been used to predict pharmacokinetic parameters from preterm neonates onwards. These models have been advocated by regulatory authorities in order to support pediatric clinical trials. The purpose of this chapter is to highlight accumulated knowledge and findings from basic research focusing on P450 enzymes, as well as the current status and future challenges of expanding the utilization of pediatric PBPK modeling.
Polymorphic cytochromes P450 in non-human primates.
Uno Y, Uehara S, Yamazaki H
Adv Pharmacol · 2022 · PMID 35953160 · Publisher ↗
Cynomolgus macaques (Macaca fascicularis, an Old World monkey) are widely used in drug development because of their genetic and physiological similarities to humans, and this trend has continued with the use of common ma...
Cynomolgus macaques (Macaca fascicularis, an Old World monkey) are widely used in drug development because of their genetic and physiological similarities to humans, and this trend has continued with the use of common marmosets (Callithrix jacchus, a New World monkey). Information on the major drug-metabolizing cytochrome P450 (CYP, P450) enzymes of these primate species indicates that multiple forms of their P450 enzymes have generally similar substrate selectivities to those of human P450 enzymes; however, some differences in isoform, activity, and substrate specificity account for limited species differences in drug oxidative metabolism. This review provides information on the P450 enzymes of cynomolgus macaques and marmosets, including cDNA, tissue expression, substrate specificity, and genetic variants, along with age differences and induction. Typical examples of important P450s to be considered in drug metabolism studies include cynomolgus CYP2C19, which is expressed abundantly in liver and metabolizes numerous drugs. Moreover, genetic variants of cynomolgus CYP2C19 affect the individual pharmacokinetic data of drugs such as R-warfarin. These findings provide a foundation for understanding each P450 enzyme and the individual pharmacokinetic and toxicological results in cynomolgus macaques and marmosets as preclinical models. In addition, the effects of induction on some drug clearances mediated by P450 enzymes are also described. In summary, this review describes genetic and acquired individual differences in cynomolgus and marmoset P450 enzymes involved in drug oxidation that may be associated with pharmacological and/or toxicological effects.
Cytochrome P450s in chimeric mice with humanized liver.
Uehara S, Suemizu H, Yamazaki H
Adv Pharmacol · 2022 · PMID 35953159 · Publisher ↗
Chimeric mice with humanized livers (humanized liver mice) are attractive experimental animal models for drug metabolism and pharmacokinetic studies. The "humanized liver" is a mature and functional liver with zonal posi...
Chimeric mice with humanized livers (humanized liver mice) are attractive experimental animal models for drug metabolism and pharmacokinetic studies. The "humanized liver" is a mature and functional liver with zonal position-specific expressions of human cytochrome P450 (P450) enzymes and a global gene expression pattern consistent with that of the mature human liver. Most P450-dependent drug oxidation activities were comparable between microsomes from livers of human and humanized liver mice based on similar expression levels of human P450 enzymes; however, some differences were observed between the two species, including considerable variations in activities of bufuralol 1'-hydroxylation and propafenone 4'-hydroxylation. Human disproportionate and/or unique metabolites of P450 substrate drugs were produced in humanized liver mice. Plasma concentration profiles of typical P450 substrate drugs in humans could be extrapolated from the corresponding data in humanized liver mice using simplified physiologically based pharmacokinetic modeling. Drug-drug interaction-mediated hepatic human CYP3A/2C induction by rifampicin (a human pregnane X receptor agonist) was observed in humanized liver mice. The major role of human CYP2C9 in in vivo diclofenac 4'-hydroxylation were determined using human CYP2C9-inactivated chimeric mice using a mechanism-based inhibitor, tienilic acid. Overall, based on the functional characteristics of hepatic human P450 enzymes, humanized liver mice are valuable experimental animals for studying metabolite profiling, pharmacokinetics, and drug interactions.
Expression and functional activity of cytochrome P450 enzymes in human hepatocytes with sustainable reproducibility for in vitro phenotyping studies.
Bachour-El Azzi P, Chesné C, Uehara S
Adv Pharmacol · 2022 · PMID 35953158 · Publisher ↗
Primary human hepatocytes are an essential in vitro tool for evaluating drug metabolism, drug-drug interactions, and hepatotoxicity. This model is considered as the gold standard in matter of DMPK studies in both industr...
Primary human hepatocytes are an essential in vitro tool for evaluating drug metabolism, drug-drug interactions, and hepatotoxicity. This model is considered as the gold standard in matter of DMPK studies in both industrial and academic research. The primary human hepatocytes are used either in suspension or in monolayer, as fresh or frozen cells. However, the use of this model is limited due to the lack of availability, rapid loss of functionality, high cost as well as the variable hepatocyte plating efficiencies in culture and the limited stock of hepatocytes derived from the same origin. Chimeric TK-NOG mice with humanized livers (humanized liver mice) are an attractive platform for drug metabolism and toxicity, which were produced by transplanting human hepatocytes into immunodeficient mice with injured livers. Here, we show that, using humanized mouse liver, in vivo human hepatocyte repopulation was over ~100-fold enabling the continuous and abundant use of human hepatocytes of the same origin and improving their plateability. In our latest cell preparations, hepatocytes isolated from humanized liver mice (Hu-Liver cells) exhibited high purity (ratio of HLA-positive cells: 92±3%), good viability (75±12%), and yield (1.0×10 cells/mouse). Human hepatic drug metabolizing enzymes, transporters, and nuclear receptors genes were expressed in humanized mouse liver. Drug-metabolizing activities in Hu-Liver cells were comparable to or higher than those in primary human hepatocytes. An extensive P450-dependent human drug metabolism was observed in Hu-Liver cells. CYP1A2, CYP2B6, and CYP3A4/5 activities/mRNA in Hu-Liver cells were induced by the hepatocyte exposure to typical human P450 inducers, omeprazole, phenobarbital, and rifampicin, respectively. Finally, Human albumin secretion and CYP3A-mediated drug oxidation activity were maintained over 4-weeks. Altogether, the expression level of pharmacokinetics-related genes, enzyme activity, human-typed drug metabolism, and inducibility of P450 in Hu-Liver cells make from humanized mouse liver a relevant and robust model for in vitro preclinical studies, including drug metabolism, pharmacokinetics, and toxicology studies.
Assessing cytochrome P450 function using genetically engineered mouse models.
Hannon SL, Ding X
Adv Pharmacol · 2022 · PMID 35953157 · Full text
The ability to knock out and/or humanize different genes in experimental animals, globally or in cell- and tissue-specific patterns, has revolutionized scientific research in many areas. Genetically engineered mouse mode...
The ability to knock out and/or humanize different genes in experimental animals, globally or in cell- and tissue-specific patterns, has revolutionized scientific research in many areas. Genetically engineered mouse models, including knockout models, transgenic models, and humanized models, have played important roles in revealing the in vivo functions of various cytochrome P450 (CYP) enzymes. These functions are very diverse, ranging from the biotransformation of drugs and other xenobiotics, events that often dictate their pharmacokinetic or toxicokinetic properties and the associated therapeutic or adverse actions, to the metabolism of endogenous compounds, such as steroid hormones and other bioactive substances, that may determine susceptibility to many diseases, such as cancer and metabolic diseases. In this review, we provide a comprehensive list of Cyp-knockout, human CYP-transgenic, and CYP-humanized mouse models that target genes in the CYP1-4 gene families, and highlight their utility in assessing the in vivo metabolism, bioactivation, and toxicity of various xenobiotic compounds, including therapeutic agents and chemical carcinogens. We aim to showcase the advantages of utilizing these mouse models for in vivo drug metabolism and toxicology studies, and to encourage and facilitate greater utility of engineered mouse models to further improve our knowledge of the in vivo functions of various P450 enzymes, which is integral to our ability to develop safer and more effective therapeutics and to identify individuals predisposed to adverse drug reactions or environmental diseases.
Use of engineered cytochromes P450 for accelerating drug discovery and development.
Thomson RES, D'Cunha SA, Hayes MA … +1 more , Gillam EMJ
Adv Pharmacol · 2022 · PMID 35953156 · Publisher ↗
Numerous steps in drug development, including the generation of authentic metabolites and late-stage functionalization of candidates, necessitate the modification of often complex molecules, such as natural products. Whi...
Numerous steps in drug development, including the generation of authentic metabolites and late-stage functionalization of candidates, necessitate the modification of often complex molecules, such as natural products. While it can be challenging to make the required regio- and stereoselective alterations to a molecule using purely chemical catalysis, enzymes can introduce changes to complex molecules with a high degree of stereo- and regioselectivity. Cytochrome P450 enzymes are biocatalysts of unequalled versatility, capable of regio- and stereoselective functionalization of unactivated CH bonds by monooxygenation. Collectively they catalyze over 60 different biotransformations on structurally and functionally diverse organic molecules, including natural products, drugs, steroids, organic acids and other lipophilic molecules. This catalytic versatility and substrate range makes them likely candidates for application as potential biocatalysts for industrial chemistry. However, several aspects of the P450 catalytic cycle and other characteristics have limited their implementation to date in industry, including: their lability at elevated temperature, in the presence of solvents, and over lengthy incubation times; the typically low efficiency with which they metabolize non-natural substrates; and their lack of specificity for a single metabolic pathway. Protein engineering by rational design or directed evolution provides a way to engineer P450s for industrial use. Here we review the progress made to date toward engineering the properties of P450s, especially eukaryotic forms, for industrial application, and including the recent expansion of their catalytic repertoire to include non-natural reactions.
Biosynthesis using cytochrome P450 enzymes: Focus on synthesis of drug metabolites.
Humphreys WG
Adv Pharmacol · 2022 · PMID 35953155 · Publisher ↗
While modern synthetic chemistry provides the ability to synthesize an incredible variety of new structures, the natural world provides unmatched chemical diversity. This diversity can be employed in the drug discovery p...
While modern synthetic chemistry provides the ability to synthesize an incredible variety of new structures, the natural world provides unmatched chemical diversity. This diversity can be employed in the drug discovery process either through isolation of an organic molecule from a biological source as a drug candidate, usually referred to as natural product chemistry, or by providing enzymes that are capable to performing chemistry not available through synthetic chemistry approaches. Natural or engineered enzymes can be used in candidate discovery to generate chemical diversity in conjunction with synthetic efforts. As a candidate progresses into develop there is often a need to characterize metabolites, thus a need for metabolite standard synthesis. Metabolite synthesis is best accomplished with a flexible application of both chemical and biosynthetic approaches. This overview of the use of biosynthesis to aid in the drug discovery and development process will cover multiple methodologies with a focus on the use of microbes as a flexible and cost-effective resource.
Atypical kinetics of cytochrome P450 enzymes in pharmacology and toxicology.
Leow JWH, Tang LWT, Chan ECY
Adv Pharmacol · 2022 · PMID 35953154 · Publisher ↗
Atypical kinetics are observed in metabolic reactions catalyzed by cytochrome P450 enzymes (P450). Yet, this phenomenon is regarded as experimental artifacts in some instances despite increasing evidence challenging the...
Atypical kinetics are observed in metabolic reactions catalyzed by cytochrome P450 enzymes (P450). Yet, this phenomenon is regarded as experimental artifacts in some instances despite increasing evidence challenging the assumptions of typical Michaelis-Menten kinetics. As P450 play a major role in the metabolism of a wide range of substrates including drugs and endogenous compounds, it becomes critical to consider the impact of atypical kinetics on the accuracy of estimated kinetic and inhibitory parameters which could affect extrapolation of pharmacological and toxicological implications. The first half of this book chapter will focus on atypical non-Michaelis-Menten kinetics (e.g. substrate inhibition, biphasic and sigmoidal kinetics) as well as proposed underlying mechanisms supported by recent insights in mechanistic enzymology. In particular, substrate inhibition kinetics in P450 as well as concurrent drug inhibition of P450 in the presence of substrate inhibition will be further discussed. Moreover, mounting evidence has revealed that despite the high degree of sequence homology between CYP3A isoforms (i.e. CYP3A4 and CYP3A5), they have the propensities to exhibit vastly different susceptibilities and potencies of mechanism-based inactivation (MBI) with a common drug inhibitor. These experimental observations pertaining to the presence of these atypical isoform- and probe substrate-specific complexities in CYP3A isoforms by several clinically-relevant drugs will therefore be expounded and elaborated upon in the second half of this book chapter.
Mammalian cytochrome P450 biodiversity: Physiological importance, function, and protein and genomic structures of cytochromes P4502B in multiple species of woodrats with different dietary preferences.
Skopec MM, Halpert JR, Dearing MD
Adv Pharmacol · 2022 · PMID 35953153 · Publisher ↗
The vast diversity of cytochrome P450 enzymes in mammals has been proposed to result in large measure from plant-animal warfare, whereby evolution of chemical defenses such as phenolics and terpenoids in plants led to du...
The vast diversity of cytochrome P450 enzymes in mammals has been proposed to result in large measure from plant-animal warfare, whereby evolution of chemical defenses such as phenolics and terpenoids in plants led to duplication and divergence of P450 genes in herbivores. Over evolutionary time, natural selection is predicted to have produced P450s with high affinity and enhanced metabolism of substrates that are ingested regularly by herbivores. Interestingly, however, almost all knowledge of the interactions of mammalian P450 enzymes with substrates stems from studies of the metabolism of drugs and model compounds rather than studies on wild mammalian herbivores and their respective PSMs. A question of particular interest centers on the role of individual P450 enzymes in the ability of certain herbivores to specialize on plants that are lethal to most other species, including those from the same genus as the specialists. We tackled this intricate problem using a tractable natural system (herbivorous woodrats, genus Neotoma) focusing on comparisons of the specialist N. stephensi, the facultative specialist N. lepida, and the generalist N. albigula, and employing a cross-disciplinary approach involving ecology, biochemistry, pharmacology, structural biology, and genomics. Based on multiple findings suggesting the importance of CYP2B enzymes for ingestion of juniper and a major constituent, α-pinene, we characterized the structure, function and activity of several CYP2B enzymes in woodrats with different dietary habits. Results to date suggest that differences in CYP2B gene copy number may contribute to differential tolerance of PSMs among woodrat species, although additional work is warranted to firmly link gene copy number to juniper tolerance.
Roles of cytochrome P450 enzymes in pharmacology and toxicology: Past, present, and future.
Guengerich FP
Adv Pharmacol · 2022 · PMID 35953152 · Full text
The development of the cytochrome P450 (P450) field has been remarkable in the areas of pharmacology and toxicology, particularly in drug development. Today it is possible to use the knowledge base and relatively straigh...
The development of the cytochrome P450 (P450) field has been remarkable in the areas of pharmacology and toxicology, particularly in drug development. Today it is possible to use the knowledge base and relatively straightforward assays to make intelligent predictions about drug disposition prior to human dosing. Much is known about the structures, regulation, chemistry of catalysis, and the substrate and inhibitor specificity of human P450s. Many aspects of drug-drug interactions and side effects can be understood in terms of P450s. This knowledge has also been useful in pharmacy practice, as well as in the pharmaceutical industry and medical practice. However, there are still basic and practical questions to address regarding P450s and their roles in pharmacology and toxicology. Another aspect is the discovery of drugs that inhibit P450 to treat diseases.
Sphingosine-1-phosphate and Sphingosine-1-phosphate receptors in the cardiovascular system: pharmacology and clinical implications.
Spampinato SF, Sortino MA, Salomone S
Adv Pharmacol · 2022 · PMID 35659378 · Publisher ↗
Sphingosine-1-phosphate (S1P) is a lipid that binds and activates five distinct receptor subtypes, S1P, S1P, S1P, S1P, S1P, widely expressed in different cells, tissues and organs. In the cardiovascular system these rece...
Sphingosine-1-phosphate (S1P) is a lipid that binds and activates five distinct receptor subtypes, S1P, S1P, S1P, S1P, S1P, widely expressed in different cells, tissues and organs. In the cardiovascular system these receptors have been extensively studied, but no drug acting on them has been approved so far for treating cardiovascular diseases. In contrast, a number of S1P receptor agonists are approved as immunomodulators, mainly for multiple sclerosis, because of their action on lymphocyte trafficking. This chapter summarizes the available information on S1P receptors in the cardiovascular system and discusses their potential for treating cardiovascular conditions and/or their role on the clinical pharmacology of drugs so far approved for non-cardiovascular conditions. Basic research has recently produced data useful to understand the molecular pharmacology of S1P and S1P receptors, regarding biased agonism, S1P storage, release and vehiculation and chaperoning by lipoproteins, paracrine actions, intracellular non-receptorial S1P actions. On the other hand, the approval of fingolimod and newer generation S1P receptor ligands as immunomodulators, provides information on a number of clinical observations on the impact of these drugs on cardiovascular system which need to be integrated with preclinical data. S1P receptors are potential targets for prevention and treatment of major cardiovascular conditions, including hypertension, myocardial infarction, heart failure and stroke.
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