Drug-oxidizing and conjugating non-cytochrome P450 (non-P450) enzymes in cynomolgus monkeys and common marmosets as preclinical models for humans

Uno, Yasuhiro; Uehara, Shotaro; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2021.114887

Cited by 9 publications

(4 citation statements)

References 100 publications

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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%

“…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%

“…Research on P450s in non-human primates (Uno et al, 2022c) and in animal models with introduced human P450 (CYP) genes or transplanted with human liver cells (Uehara et al, 2022) has extended into different fields, from molecular to in vivo research. The present minireview summarizes recent findings on polymorphic P450-and FMO-mediated oxidation and bioactivation reactions.…”

Section: Introductionmentioning

confidence: 99%

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

Yamazaki

Shimizu

2023

Drug Metabolism and Disposition

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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%

Section: Perspective On Future Directionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yamazaki

Shimizu

2023

Drug Metabolism and Disposition

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“…Over the past two decades, marmosets have been more frequently used in preclinical, toxicology, and safety assessment of drugs. 4-30…”

Section: Introductionmentioning

confidence: 99%

The Common Marmoset—Biomedical Research Animal Model Applications and Common Spontaneous Diseases

Han

2022

Toxicol Pathol

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Marmosets are becoming more utilized in biomedical research due to multiple advantages including (1) a nonhuman primate of a smaller size with less cost for housing, (2) physiologic similarities to humans, (3) translatable hepatic metabolism, (4) higher numbers of litters per year, (5) genome is sequenced, molecular reagents are available, (6) immunologically similar to humans, (7) transgenic marmosets with germline transmission have been produced, and (8) are naturally occurring hematopoietic chimeras. With more use of marmosets, disease surveillance over a wide range of ages of marmosets has been performed. This has led to a better understanding of the disease management of spontaneous diseases that can occur in colonies. Knowledge of clinical signs and histologic lesions can assist in maximizing the colony’s health, allowing for improved outcomes in translational studies within biomedical research. Here, we describe some basic husbandry, biology, common spontaneous diseases, and animal model applications for the common marmoset in biomedical research.

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A variety of cytochrome P450 enzymes and flavin-containing monooxygenases in dogs and pigs commonly used as preclinical animal models

Uno,

Shimizu,

Yamazaki

2024

Biochemical Pharmacology

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Drug-oxidizing and conjugating non-cytochrome P450 (non-P450) enzymes in cynomolgus monkeys and common marmosets as preclinical models for humans

Cited by 9 publications

References 100 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

The Common Marmoset—Biomedical Research Animal Model Applications and Common Spontaneous Diseases

A variety of cytochrome P450 enzymes and flavin-containing monooxygenases in dogs and pigs commonly used as preclinical animal models

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