The marmoset cytochrome P450 superfamily: Sequence/phylogenetic analyses, genomic structure, and catalytic function

Uehara, Shotaro; Uno, Yasuhiro; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2019.113721

Cited by 14 publications

(6 citation statements)

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“…Because FMOs are not readily induced or inhibited, it has been suggested that there may be advantages in designing drugs that are partly metabolized by FMOs, i.e., drugs that are not metabolized exclusively by P450s (Krueger and Williams, 2005;Cashman, 2008). However, the contributions of FMOs to the metabolic elimination of new drug candidates may be underestimated under the usual experimental and physiological conditions of pH 7.4, which are more suited to P450 enzymes initiated by the addition of NADPH to reaction mixtures containing drug candidates with classic dissociation constants (pK a base) of >8.4 (Taniguchi-Takizawa et al, 2021) Utility of non-human primates in drug development because of their physiological and genetic similarities to humans has been separately reviewed with information on the major multiple forms of drug-metabolizing P450 enzymes and FMO3 having generally similar substrate selectivities to those of human P450s and FMO3 (Uno et al, 2016;Uno et al, 2018;Uehara et al, 2020;Uno et al, 2022c).…”

Section: Dmdmentioning

confidence: 99%

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Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

Yamazaki

Shimizu

2022

Drug Metab Dispos

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Many drug oxygenations are mainly mediated by polymorphic cytochromes P450 (P450s) and also by flavin-containing monooxygenases (FMOs). More than 50 years of research on P450/FMO-mediated drug oxygenations have clarified their catalytic roles. The natural product coumarin causes hepatotoxicity in rats via the reactive coumarin 3,4-epoxide, a reaction catalyzed by P450 1A2; however, coumarin undergoes rapid 7-hydroxylation by polymorphic P450 2A6 in humans. The primary oxidation product of the teratogen thalidomide in rats is deactivated 5′-hydroxythalidomide plus sulfate and glucuronide conjugates; however, similar 5′-hydroxythalidomide and 5-hydroxythalidomide are formed in rabbits in vivo. Thalidomide causes human P450 3A enzyme induction in liver (and placenta) and is also activated in vitro and in vivo by P450 3A through the primary human metabolite 5-hydroxythalidomide (leading to conjugation with glutathione/nonspecific proteins). Species differences exist in terms of drug metabolism in rodents and humans, and such differences can be very important when determining the contributions of individual enzymes. The approaches used for investigating the roles of human P450 and FMO enzymes in understanding drug oxidations and clinical therapy have not yet reached maturity and still require further development.

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Section: Dmdmentioning

confidence: 99%

“…To facilitate extrapolation of the in vivo pharmacokinetics of drugs from data obtained in non-human primates to humans, polymorphic drug oxygenation enzymes were investigated in monkeys and marmosets (Uno et al, 2016;Uno et al, 2018;Uehara et al, 2020;Uno et al, 2022c).…”

Section: Perspective On Future Directionsmentioning

confidence: 99%

Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

Yamazaki

Shimizu

2022

Drug Metab Dispos

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“…To date, 36 C. jacchus CYP isoenzymes (cjCYP) have been identified and 24 of them, belonging to 1A, 2A, 2B, 2C, 2D, 2E, 3A, 4A, and 4F subfamilies, share a high degree of homology in the cDNA (>89%) and amino acid sequences (>85%) with corresponding human P450s [ 180 ]. Among these, CYP1A2, 2A6, 2B6, four 2C subfamily members (2C8, 2C18, 2C19 and 2C58), 2D6, 2D8, 2E1, 2J2, 3A4, 3A5, 4A11, 4F2, 4F12 and 7B1 are expressed in the marmoset liver [ 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 ].…”

Section: Drug Metabolism Studies With Marmoset Esc-derived Hlcsmentioning

confidence: 99%

“…Among these, CYP1A2, 2A6, 2B6, four 2C subfamily members (2C8, 2C18, 2C19 and 2C58), 2D6, 2D8, 2E1, 2J2, 3A4, 3A5, 4A11, 4F2, 4F12 and 7B1 are expressed in the marmoset liver [ 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 ]. Interestingly, CYP1D1 , encoded by a pseudogene in human liver is also pseudogenized in C. jacchus due to an incomplete open reading frame [ 180 ]. Induction studies have shown similar patterns between the common marmoset and human CYP orthologs.…”

Section: Drug Metabolism Studies With Marmoset Esc-derived Hlcsmentioning

confidence: 99%

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

Aravalli

Steer

2020

Genes

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The incidence of liver disease is increasing significantly worldwide and, as a result, there is a pressing need to develop new technologies and applications for end-stage liver diseases. For many of them, orthotopic liver transplantation is the only viable therapeutic option. Stem cells that are capable of differentiating into all liver cell types and could closely mimic human liver disease are extremely valuable for disease modeling, tissue regeneration and repair, and for drug metabolism studies to develop novel therapeutic treatments. Despite the extensive research efforts, positive results from rodent models have not translated meaningfully into realistic preclinical models and therapies. The common marmoset Callithrix jacchus has emerged as a viable non-human primate model to study various human diseases because of its distinct features and close physiologic, genetic and metabolic similarities to humans. C. jacchus embryonic stem cells (cjESC) and recently generated cjESC-derived hepatocyte-like cells (cjESC-HLCs) could fill the gaps in disease modeling, liver regeneration and metabolic studies. They are extremely useful for cell therapy to regenerate and repair damaged liver tissues in vivo as they could efficiently engraft into the liver parenchyma. For in vitro studies, they would be advantageous for drug design and metabolism in developing novel drugs and cell-based therapies. Specifically, they express both phase I and II metabolic enzymes that share similar substrate specificities, inhibition and induction characteristics, and drug metabolism as their human counterparts. In addition, cjESCs and cjESC-HLCs are advantageous for investigations on emerging research areas, including blastocyst complementation to generate entire livers, and bioengineering of discarded livers to regenerate whole livers for transplantation.

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“…As mentioned, Cyt P450s metabolize drugs and other chemicals in humans, but in some cases produce toxic products. 7,[14][15][16][17][18][19] Cyt P450s are biocatalysts for C-H hydroxylation, N-and S-oxidation, O-, N-and S-dealkylation, C-C bond cleavage, CQC double bond epoxidation, aromatic coupling, as well as more unusual reactions. 20,21 They are effective for synthesis of drugs, drug metabolites, [22][23][24][25][26][27] bioremediation, [28][29][30] and development of biosensors.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical transformations catalyzed by cytochrome P450s and peroxidases

Kumar

Rusling

2023

Chem. Soc. Rev.

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The marmoset cytochrome P450 superfamily: Sequence/phylogenetic analyses, genomic structure, and catalytic function

Cited by 14 publications

References 94 publications

Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

Electrochemical transformations catalyzed by cytochrome P450s and peroxidases

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