Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation

Hosoi, Yoshio; Uno, Yasuhiro; Murayama, Norie; Fujino, Hideki; Shukuya, Mitsunori; Iwasaki, Katsunori; Shimizu, Makiko; Utoh, Masahiro; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2012.09.026

Cited by 20 publications

(23 citation statements)

References 24 publications

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“…Racemic warfarin was metabolized to 7-and 6-hydroxywafarin in marmosets in vivo in a similar manner to humans . The similar stereoselectivity for warfarin 7-hydroxylation between marmosets and humans was supported by drug-metabolizing properties of marmoset P450 2C19 and human P450 2C9 (Yamazaki and Shimada, 1997;Hosoi et al, 2012;Uehara et al, 2015). In this study, the metabolic clearance of S-warfarin with a large interindividual variation was mediated by polymorphic marmoset P450 2C19 enzymes involved in drug oxidations (Fig.…”

Section: Discussionsupporting

confidence: 64%

“…The well established and clinically important anticoagulant drug S-warfarin is a typical human P450 2C9 substrate (Yamazaki and Shimada, 1997). Cynomolgus monkey P450 2C19 has high activity toward R-warfarin 7-hydroxylation (Hosoi et al, 2012), whereas marmoset P450 2C19 efficiently catalyzes S-warfarin 7-hydroxylation . Interanimal variations of R-warfarin clearance in cynomolgus monkeys are accounted for by the monkey P450 2C19 genetic variant p.[(Phe100Asn; Ala103Val; Ile112Leu)] (Uno et al, 2014a;Utoh et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Uehara

Uno

Inoue

et al. 2016

Drug Metabolism and Disposition

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Marmoset cytochrome P450 2C19, highly homologous to human P450 2C9 and 2C19, has been identified in common marmosets (Callithrix jacchus), a nonhuman primate species used in drug metabolism studies. Although genetic variants in human and macaque P450 2C genes account for the interindividual variability in drug metabolism, genetic variants have not been investigated in the marmoset P450 2C19. In this study, sequencing of P450 2C19 in 24 marmosets identified three variants p.[(Phe7Leu; Ser254Leu; Ile469Thr)], which showed substantially reduced metabolic capacity of S-warfarin compared with the wild-type group in vivo and in vitro. Although mean plasma concentrations of R-warfarin in marmosets determined after chiral separation were similar between the homozygous mutant and wild-type groups up to 24 hours after the intravenous and oral administrations of racemic warfarin, S-warfarin depletion from plasma was significantly faster in the three wild-type marmosets compared with the three homozygous mutant marmosets. These variants, cosegregating in the marmosets analyzed, influenced metabolic activities in 18 marmoset liver microsomes because the homozygotes and heterozygotes showed significantly reduced catalytic activities in liver microsomes toward S-warfarin 7-hydroxylation compared with the wild-type group. Kinetic analysis for S-warfarin 7-hydroxylation indicated that the recombinant P450 2C19 Ser254Leu variant would change the metabolic capacity. These results indicated that the interindividual variability of P450 2C-dependent drug metabolism such as S-warfarin clearance is at least partly accounted for by P450 2C19 variants in marmosets, suggesting that polymorphic P450 2C-dependent catalytic functions are relatively similar between marmosets and humans.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Uehara

Uno

Inoue

et al. 2016

Drug Metabolism and Disposition

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“…R-and S-warfarin and 7-hydroxywarfarin were obtained from Ultrafine Chemicals (Manchester, UK). Drug-metabolizing activities of CYP2C19 proteins were assessed using caffeine, diclofenac, flurbiprofen, omeprazole, and R-/S-warfarin as substrate as described previously [12][13][14][15]. Briefly, a typical mixture (0.25 ml) contained recombinant CYP2C19 protein (2.5-20 pmol) or liver microsomes (0.05-0.25 mg), an NADPH-generating system (0.25 mM NADP + , 2.5 mM glucose 6-phosphate, and 0.25 unit/ml glucose-6-phosphate dehydrogenase), and substrate (500 mM caffeine, 50 mM diclofenac, 20 mM flurbiprofen, 10 mM omeprazole, 200 mM S-mephenytoin or 10 mM S-or R-warfarin unless otherwise specified) in 50 mM potassium phosphate buffer (pH 7.4).…”

Section: Enzymatic Characterizationmentioning

confidence: 99%

CYP2C19 polymorphisms account for inter-individual variability of drug metabolism in cynomolgus macaques

Uno

Matsushita

Shukuya

et al. 2014

Biochemical Pharmacology

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“…We reported previously that S-warfarin 7-hydroxylation in human liver microsomes was mainly catalyzed by P450 2C9, although cynomolgus monkey P450 2C19 preferentially catalyzed 7-hydroxylation of R-warfarin (Hosoi et al, 2012). Among all marmoset P450 2C enzymes, marmoset P450 2C19 efficiently catalyzed 7-hydroxylation for S-warfarin, but not R-warfarin, similar to human P450 2C9 (Table 4).…”

Section: Discussionmentioning

confidence: 67%

“…Monkey P450 2C9 and 2C19 share similar metabolic properties with human P450 2C9 and 2C19 in the metabolism of tolbutamide, S-mephenytoin, flurbiprofen, and diclofenac (Uno et al, 2011b). P450 2C19 stereoselectively catalyzes R-warfarin 7-hydroxylation (Hosoi et al, 2012). Cynomolgus monkey P450 2C76, not orthologous to human P450s, catalyzes tolbutamide methyl hydroxylation and is partly responsible for the differences in drug metabolism between macaques and humans (Uno et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

Novel Marmoset Cytochrome P450 2C19 in Livers Efficiently Metabolizes Human P450 2C9 and 2C19 Substrates, S-Warfarin, Tolbutamide, Flurbiprofen, and Omeprazole

Uehara

Uno

Inoue

et al. 2015

Drug Metabolism and Disposition

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The common marmoset (Callithrix jacchus), a small New World monkey, has the potential for use in human drug development due to its evolutionary closeness to humans. Four novel cDNAs, encoding cytochrome P450 (P450) 2C18, 2C19, 2C58, and 2C76, were cloned from marmoset livers to characterize P450 2C molecular properties, including previously reported P450 2C8. The deduced amino acid sequence showed high sequence identities (>86%) with those of human P450 2Cs, except for marmoset P450 2C76, which has a low sequence identity (∼70%) with any human P450 2Cs. Phylogenetic analysis showed that marmoset P450 2Cs were more closely clustered with those of humans and macaques than other species investigated. Quantitative polymerase chain reaction analysis showed that all of the marmoset P450 2C mRNAs were predominantly expressed in liver as opposed to the other tissues tested. Marmoset P450 2C proteins were detected in liver by immunoblotting using antibodies against human P450 2Cs. Among marmoset P450 2Cs heterologously expressed in Escherichia coli, marmoset P450 2C19 efficiently catalyzed human P450 2C substrates, S-warfarin, diclofenac, tolbutamide, flurbiprofen, and omeprazole. Marmoset P450 2C19 had high V max and low K m values for S-warfarin 7-hydroxylation that were comparable to those in human liver microsomes, indicating warfarin stereoselectivity similar to findings in humans. Faster in vivo S-warfarin clearance than R-warfarin after intravenous administration of racemic warfarin (0.2 mg/kg) to marmosets was consistent with the in vitro kinetic parameters. These results indicated that marmoset P450 2C enzymes had functional characteristics similar to those of humans, and that P450 2C-dependent metabolic properties are likewise similar between marmosets and humans.

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Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation

Cited by 20 publications

References 24 publications

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

CYP2C19 polymorphisms account for inter-individual variability of drug metabolism in cynomolgus macaques

Novel Marmoset Cytochrome P450 2C19 in Livers Efficiently Metabolizes Human P450 2C9 and 2C19 Substrates, S-Warfarin, Tolbutamide, Flurbiprofen, and Omeprazole

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