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

Abstract

Drug oxygenation is mainly mediated by cytochromes P450 (P450s, CYPs) and flavin-containing monooxygenases (FMOs). Polymorphic variants of P450s and FMOs are known to influence drug metabolism. Species differences exist in terms of drug metabolism and can be important when determining the contributions of individual enzymes. The success of research into drug-metabolizing enzymes and their impacts on drug discovery and development has been remarkable. Dogs and pigs are often used as preclinical animal models. This research update provides information on P450 and FMO enzymes in dogs and pigs and makes comparisons with their human enzymes. Newly identified dog CYP3A98, a testosterone 6β- and estradiol 16α-hydroxylase, is abundantly expressed in small intestine and is likely the major CYP3A enzyme in small intestine, whereas dog CYP3A12 is the major CYP3A enzyme in liver. The roles of recently identified dog CYP2J2 and pig CYP2J33/34/35 were investigated. FMOs have been characterized in humans and several other species including dogs and pigs. P450 and FMO family members have been characterized also in cynomolgus macaques and common marmosets. P450s have industrial applications and have been the focus of attention of many pharmaceutical companies. The techniques used to investigate the roles of P450/FMO enzymes in drug oxidation and clinical treatments have not yet reached maturity and require further development. The findings summarized here provide a foundation for understanding individual pharmacokinetic and toxicological results in dogs and pigs as preclinical models and will help to further support understanding of the molecular mechanisms of human P450/FMO functionality.

Keywords: Dog; FMO; P450; Pig.