Genetic Variants of<i>CYP3A4</i>and<i>CYP3A5</i>in Cynomolgus and Rhesus Macaques

Uno, Yasuhiro; Matsushita, Akinori; Osada, Naoki; Uehara, Shotaro; Kohara, Saori; Nagata, Ryoichi; Fukuzaki, Koichiro; Utoh, Masahiro; Murayama, Norie; Yamazaki, Hiroshi

doi:10.1124/dmd.109.029710

Cited by 54 publications

(58 citation statements)

References 20 publications

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“…Several studies have demonstrated that monkeys are particularly useful in interspecies scaling for predicting human pharmacokinetics (Ward and Smith, 2004;Ward et al, 2005;Sakuda et al, 2006;Ogasawara et al, 2007). Recent studies have identified a number of P450 cDNAs from cynomolgus monkeys, including those of CYP3A8 and CYP3A5, which show high sequence identities (94 -95%) with the orthologous human CYP3A4 and CYP3A5, respectively (Uno et al, 2007(Uno et al, , 2010Iwasaki and Uno, 2009). Furthermore, when an oral dose of CYP3A substrates, such as midazolam (MDZ) and simvastatin, was coadministered with typical CYP3A inhibitors, these monkeys showed markedly higher plasma concentrations than those who received a dose of substrate alone (Kanazu et al, 2004;Ogasawara et al, 2007Ogasawara et al, , 2009a.…”

Section: Introductionmentioning

confidence: 99%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Induction of the cytochrome P450 (P450) enzyme is a major concern in the drug discovery processes. To predict the clinical significance of enzyme induction, it is helpful to investigate pharmacokinetic alterations of a coadministered drug in a suitable animal model. In this study, we focus on the induction of CYP3A, which is involved in the metabolism of approximately 50% of marketed drugs and is inducible in both the liver and intestine. As a marker substrate for CYP3A activity, alprazolam (APZ) was selected and characterized using recombinant CYP3A enzymes expressed in Escherichia coli. Both human CYP3A4 and its cynomolgus P450 ortholog predominantly catalyzed APZ 4-hydroxylation with sigmoidal kinetics. When administered intravenously and orally to cynomolgus monkeys, APZ had moderate clearance; its first-pass extraction ratio after oral dosing was estimated to be 0.09 in the liver and 0.45 in the intestine. Pretreatment with multiple doses of rifampicin (20 mg/kg p.o. for 5 days), a known CYP3A inducer, significantly decreased plasma concentrations of APZ after intravenous and oral administrations (0.5 mg/kg), and first-pass extraction ratios were increased to 0.39 in the liver and 0.63 in the intestine. The results were comparable to those obtained in clinical drug-drug interaction (DDI) reports related to CYP3A induction, although the rate of recovery of CYP3A activity seemed to be slower than rates estimated in clinical studies. In conclusion, pharmacokinetic studies using APZ as a probe in monkeys may provide useful information regarding the prediction of clinical DDIs due to CYP3A induction.

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Section: Introductionmentioning

confidence: 99%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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“…A previous study also found many genetic variants in a large number of genes were shared between the two lineages [13], including CYP3A4 and CYP3A5 [15]. On the other hand, 12 and 5 genetic variants were unique to cynomolgus and rhesus macaques, respectively (Table 2).…”

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confidence: 77%

“…Expression of macaque CYP1B1 mRNA has been detected in brain regions, including frontal cortex, hippocampus, thalamus, and amygdala [8]. Since macaques have a diverse genetic background, similar to human, as evidenced by identification of genetic variants in a number of genes, including CYPs [15,16], macaques might possess numerous CYP1B1 genetic variants. Some variants could account for inter-animal differences in CYP1B1-dependent metabolism of promutagens, making it difficult to interpret the data obtained.…”

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confidence: 99%

“…This study was reviewed and approved by the Institutional Animal Care and Use Committee of Shin Nippon Biomedical Laboratories, Ltd (Kainan, Japan). Each genome sample was used as a template for polymerase chain reaction (PCR) that was carried out as described previously [15]. Briefly, PCR was performed in a 20-l reaction containing 1 ng of genomic DNA, 5 pmole of each primer, and 1 unit of EX Taq HS DNA polymerase (Takara, Tokyo, Japan), using a thermal cycler (Applied Biosystems, Foster City, CA).…”

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confidence: 99%

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CYP1B1 is Polymorphic in Cynomolgus and Rhesus Macaques

Uno

Matsushita

Yamazaki

2011

The Journal of Veterinary Medical Science

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ABSTRACT. Cytochrome P450 (CYP) 1B1 is involved in the metabolic activation of various procarcinogens, and some CYP1B1 genetic variants alter CYP1B1-dependent procarcinogen metabolism. Cynomolgus and rhesus macaques are frequently used in toxicity tests due to their evolutionary closeness to humans. In this study, we attempted to identify CYP1B1 genetic variants in 13 cynomolgus and 4 rhesus macaques. A total of 17 genetic variants were identified, including 8 non-synonymous genetic variants, indicating that, similar to humans, CYP1B1 is polymorphic in macaques. These CYP1B1 genetic variants could be the basis for understanding potential interanimal differences in macaque CYP1B1-dependent metabolism of promutagens.KEY WORDS: CYP1B1, cytochrome P450, genetic variants, macaque.J. Vet. Med. Sci. 73(9): 1229-1231, 2011 Cytochrome P450 (CYP) 1B1 belongs to the CYP1 family, which also consists of CYP1A1 and CYP1A2 in human. CYP1B1, and CYP1A1, play a major role in the activation of most carcinogenic polycyclic aromatic hydrocarbons [7]. Human CYP1B1 is expressed in the extrahepatic tissues, including kidney, thymus, spleen, lung, colon, intestine, uterus, mammary gland, ovary, and prostate [10]. Genetic variants have been identified in human CYP1B1, some of which are important for CYP1B1 function [11]. For example, a previous study showed that L432V increased the catalytic activity of human CYP1B1 [1,6], probably due to alterations in the tertiary or quaternary structure of the CYP1B1 protein [11], and that N453S is associated with a decrease in protein expression due to increased degradation of CYP1B1 protein [2]. The CYP1B1*3 haplotype is associated with an elevated expression of CYP1B1 mRNA in lymphocytes that are treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin [5]. Moreover, several CYP1B1 genotypes have been associated with an increased risk of cancer: L432V with breast, endometrial, ovarian, and prostate cancer; A119S with endometrial and prostate cancer; N453S with endometrial cancer [11].Macaques, including cynomolgus macaque (Macaca fascicularis) and rhesus macaque (Macaca mulatta), are frequently used in biomedical research, including toxicology and neuroscience, due to their evolutionary closeness to humans. In macaques, metabolic activation of carcinogen such as 2-amino-3-methylimidazo[4,5-f]quinoline, which is partly mediated by CYP1B1 in human, results in DNA adduct formation and carcinogenesis in liver and development of hepatocelluler carcinoma [9]. Numerous CYPs have been identified in cynomolgus macaque and rhesus macaque, and are highly identical (generally >99%) in amino acids between the two lineages [14]. Expression of macaque CYP1B1 mRNA has been detected in brain regions, including frontal cortex, hippocampus, thalamus, and amygdala [8]. Since macaques have a diverse genetic background, similar to human, as evidenced by identification of genetic variants in a number of genes, including CYPs [15,16], macaques might possess numerous CYP1B1 genetic variants. Some variants could account for inter-...

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“…Macaque CYP3A8(4) metabolizes typical human CYP3A4 substrates such as midazolam and nifedipine (Iwasaki et al, 2010;Uno et al, 2010) and is induced by the typical human CYP3A4 inducer, rifampicin (Kim et al, 2010), indicating that CYP3A8(4) has drug-metabolizing enzyme properties similar to human CYP3A4. Induction of cynomolgus macaque CYP3A8(4) and human CYP3A4 by rifampicin is mediated via PXR (Kim et al, 2010), which binds to the regulatory element in the upstream region of CYP3A4, suggesting that the regulatory region of cynomolgus macaque CYP3A8(4) and human CYP3A4 is conserved well between macaque and human.…”

Section: Estradiol-regulated Drug-metabolizing Enzymes In Macaquementioning

confidence: 99%

Effect of Estradiol on Gene Expression Profile in Cynomolgus Macaque Liver: Implications for Drug-Metabolizing Enzymes

Uno

Kito²

2011

Drug Metab Dispos

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ABSTRACT:Estrogen regulation of gene expression is essential for physiological function of estrogen-responsive tissues, such as mammary glands, ovaries, and the uterus. In the liver, estrogen is responsible for sex-dependent gene expression of drug-metabolizing enzymes in rodents. However, the influence of estrogen on hepatic gene expression has not been fully investigated in primates, including human. Macaque, including cynomolgus macaque, is an important species for comparative studies aimed at understanding human physiology due to its evolutionary closeness to human. To identify estrogen-responsive genes in primate liver, therefore, hepatic gene expression was compared, by microarray analysis, in ovariectomized cynomolgus macaques treated with estradiol or solvent (control). The analysis identified 98 estradiol-responsive genes; 47 and 51 were up-and down-regulated by estradiol, respectively (>2.0-fold, P < 0.05). Expression of drug-metabolizing enzyme genes was also influenced by estradiol treatment; estradiol enhanced expression of GSTM5 (3.8-fold, P < 0.05) and CYP3A8(4) (2.7-fold, P < 0.01), but lowered expression of CYP4F12 (2.2-fold, P < 0.01), as verified by quantitative polymerase chain reaction. In particular, CYP3A8(4), orthologous to human CYP3A4, is an essential drug-metabolizing enzyme in cynomolgus macaque liver. These results suggest that expression of hepatic genes, including drug-metabolizing enzyme genes, is at least partly regulated by estradiol in cynomolgus macaque.

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Genetic Variants ofCYP3A4andCYP3A5in Cynomolgus and Rhesus Macaques

Cited by 54 publications

References 20 publications

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

CYP1B1 is Polymorphic in Cynomolgus and Rhesus Macaques

Effect of Estradiol on Gene Expression Profile in Cynomolgus Macaque Liver: Implications for Drug-Metabolizing Enzymes

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