Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers

Yamaori, Satoshi; Yamazaki, Hiroshi; Iwano, Shunsuke; Kiyotani, Kazuma; Matsumura, K.; Saito, Tetsuya; Parkinson, Andrew; Nakagawa, Kazuko; Kamataki, Tetsuya

doi:10.1080/00498250400021796

Cited by 57 publications

(42 citation statements)

References 30 publications

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“…Microsomal protein concentrations were estimated by using a bicinchoninic acid protein assay kit (Pierce, Rockford, IL). Concentrations of total P450 (Omura and Sato, 1964) and NADPH-P450 reductase (EC 1.6.2.4) (Yamazaki et al, 2002) as well as P450 3A4 and 3A5 contents in liver microsomes (Yamaori et al, 2005) were determined as described previously. The liver microsomal samples HL-1 and HL-3 contained 18 pmol P450 3A4 and 6.1 pmol P450 3A5 per mg of protein and 17 pmol P450 3A4 and 24 pmol P450 3A5 per mg of protein, respectively (Yamaori et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Okada

Murayama²,

Yanagida³

et al. 2008

Drug Metab Dispos

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ABSTRACT:There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 (P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. Thalidomide inhibited S-mephenytoin 4-hydroxylation activities of recombinant P450 2C19 and human liver microsomes: the apparent concentration of thalidomide producing 50% inhibition was approximately 270 M for P450 2C19. Midazolam 4-hydroxylation activities were suppressed by thalidomide, but activities of 1-hydroxylation and total midazolam oxidation and testosterone 6␤-hydroxylation were enhanced in the presence of thalidomide. Recombinant P450 3A5 was found to have altered kinetics at clinically relevant concentrations of thalidomide (10-30 M). P450 3A4 was also affected, but only at higher thalidomide concentrations. Enhanced midazolam hydroxylation by thalidomide was also seen in liver microsomal samples harboring the CYP3A5*1 allele. Similarly enhanced rates of cyclosporine A clearance were observed in P450 3A5 and liver microsomes expressing P450 3A5 in the presence of thalidomide. A proposed effector constant for thalidomide corresponded roughly to its clinical plasma levels. Docking studies with a P450 3A5 homology model, based on the published structure of P450 3A4, revealed close interaction between thalidomide and the heme of P450 3A5. The present results suggest that total midazolam metabolism or cyclosporine A clearance may be increased by thalidomide in a dose-dependent manner. Unexpected drug interactions involving thalidomide might occur via heterotropic cooperativity of polymorphic P450 3A5.

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Section: Methodsmentioning

confidence: 99%

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Okada

Murayama²,

Yanagida³

et al. 2008

Drug Metab Dispos

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“…CYP3A4 is the most abundant P450 enzyme in human liver responsible for the metabolism of 50% of clinical drugs 17) . Ethnic differences in the regulation mechanism and expression levels of CYP3A4 between Japanese and Caucasian subjects have been reported 18) and a significant difference in the frequency of CYP3A4 variants across the ethnic groups. Caucasians have a higher frequency of CYP3A4-2 and-7, whereas Asian populations have higher frequencies of variants 16 and 18 19,20) .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects

Täubel¹,

Sumeray

Lorch³

et al. 2016

J Atheroscler Thromb

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Aims: Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolaemia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Caucasian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses. Methods: In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥ 110 mg/dL were administered an escalating lomitapide dose range of 10 -60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels. Results: Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10 -60 mg for both single-and multiple-dose administration. The correlation between AUC0-t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomitapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders. Conclusions: Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.J Atheroscler Thromb, 2016; 23: 606-620.

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“…On the other hand, CYPIA2 shows a mean higher activity in African-Americans and in Caucasians than in Hispanics (32). Liver CYP3A4 is expressed 3 times more in the Japanese population than in Caucasians; Cyp3A5 and CYP3A7 are expressed twice as much in the liver of adult Japanese people than in Caucasians (33).…”

Section: Interindividual and Interethnic Variability In The Expressiomentioning

confidence: 99%

Cytochrome P450 Genetic Polymorphism in Neonatal Drug Metabolism: Role and Practical Consequences towards a New Drug Culture in Neonatology

Fanni

Ambu

Gerosa

et al. 2014

Int J Immunopathol Pharmacol

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The cytochrome P450 superfamily (CYP450) in humans is formed by 57 functional monooxygenases critical for the metabolism of numerous endogenous and exogenous compounds. The superfamily is organized into 18 families and 44 subfamilies. CYP nomenclature is based on the identity of amino acids. The most important functions of the CYP450 are related to metabolism of endogenous compounds, detoxification of exogenous xenobiotics and decomposition of the vast majority of currently used drugs. The expression of CYP450 enzymes in the human body is characterized by a marked substrate and tissue specificity, the most important being localized in the liver, but also present in kidney, lung, brain, breast, prostate and in the small intestine. The human cytochrome P450 3A gene family (CYP3A) accounts for the largest portion of CYP450 proteins in human liver and includes 4 genes: CYP3A4, CYP3A5, CYP3A7, CYP3A43. Multiple and complex genetic variations, marked interindividual, interethnic and gender variability have been reported regarding CYP3A isoform expression and activity. Multiple factors may affect CYP3A expression and activity, such as inducers like rifampicin, phenobarbital, 3-methylcholantrene, beta-naphtoflavone, and dexamethasone. The maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of postnatal life, surely exerts profound effects on drug disposition, probably being the predominant factor accounting for age-associated changes in drug clearance. In fact, drug dosage in the perinatal period represents a continuous challenge for neonatologists. The purpose of this article is to provide a brief review of the pharmacokinetic differences between neonates and adults, showing the peculiarities of liver CYP450-related drug metabolism in the perinatal period and at birth, and to report the toxic mechanisms of liver injury in neonates, due to the most frequently utilized drugs in NICU centers.Drug dosage in the perinatal period represents a continuous challenge for neonatologists, particularly for those involved in neonatal intensive care unit (NICU) centers. In fact, the maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of

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Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers

Cited by 57 publications

References 30 publications

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects

Cytochrome P450 Genetic Polymorphism in Neonatal Drug Metabolism: Role and Practical Consequences towards a New Drug Culture in Neonatology

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