Cited by 2,785Pharmacogenetics and Drug MetabolismDrug-Induced Hepatotoxicity and ProtectionMetal-Catalyzed Oxygenation Mechanisms

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Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians

Shimada, T, Yamazaki, H, Mimura, M, Inui, Y, Guengerich, F P·1994·The Journal of Pharmacology and Experimental Therapeutics

DOI 10.1016/s0022-3565(25)22379-5

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Abstract

Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 (about 4%), 2D6 (about 2%) and 2B6 (< 1%) were the minor P-450 forms. Differences in some of the P-450 1A2-, 2A6-, 2D6-, 2E1- and 3A4-dependent activities were observed in Japanese and Caucasian populations. No clear sex-related differences in individual P-450 contents and drug- and carcinogen-metabolizing activities were detected in 60 human samples, except that P-450 1A2-dependent activities were found to be higher in mean than in women in the Caucasian population only. A single neonate sample tended to be lower in P-450 1A2-, 2A6- and 2E1-dependent activities. In contrast to rat counterparts, we could not detect apparent developmental changes in P-450 content and activity in humans between 12 and 73 years old. Thus, the results presented in this study provide useful information for the study of drug biotransformation in humans and for the basis of drug toxicities, carcinogenesis and teratogenesis.

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Identification and Characterization of Human Cytochrome P450 Isoforms Interacting with Pimozide
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In Vitro/in Vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans
Hirota, N., Ito, K., Iwatsubo, T., Green, C. E., Tyson, C. A., Shimada, N., Suzuki, H., & Sugiyama, Y. (2001) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.261 · Cited by 74
“CYP3A accounts for about 30% of total CYP in human liver (96 pmol/ mg microsomal (MS) protein) [6].”
Background
Specific features of pharmacokinetics in children
Matalová, P., Urbánek, K., & Anzenbacher, P. (2016) · Drug Metabolism Reviews · doi:10.3109/03602532.2015.1135941 · Cited by 73
“CYP2E1 constitutes approximately 7% of the total hepatic CYP enzymes and is involved in the metabolism of approximately 75 compounds of various structures (Shimada et al., 1994).”
Background
DNA methylation dynamics in the hepatic CYP3A4 gene promoter
Kacevska, M., Ivanov, M., Wyss, A., Kasela, S., Milani, L. A., Rane, A., & Ingelman‐Sundberg, M. (2012) · Biochimie · doi:10.1016/j.biochi.2012.07.013 · Cited by 74
Opioid Therapies and Cytochrome P450 Interactions
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Cytochrome P450 metabolic dealkylation of nine N-nitrosodialkylamines by human liver microsomes
Bellec, G., Dréano, Y., Lozach, P., Menez, J. F., & Berthou, F. (1996) · Carcinogenesis · doi:10.1093/carcin/17.9.2029 · Cited by 71
Abundance of Hepatic Transporters in Caucasians: A Meta-Analysis
Burt, H. J., Riedmaier, A. E., Harwood, M., Crewe, H., Gill, K. L., & Neuhoff, S. (2016) · Drug Metabolism And Disposition · doi:10.1124/dmd.116.071183 · Cited by 78
“The availability of recombinant P450 standards has facilitated the quantification of a wide range of P450 isoenzyme abundances in human liver samples, typically by immunoblotting techniques (Shimada et al., 1994; Rowland-Yeo et al., 2004).”
Background
Specificity of 17β-oestradiol and benzo[α]pyrene oxidation by polymorphic human cytochrome P4501B1 variants substituted at residues 48, 119 and 432
Shimada, T., Watanabe, J. A., Inoue, K., et al. (2001) · Xenobiotica · doi:10.1080/00498250110043490 · Cited by 74
“Other chemicals and reagents used were from sources described previously or were of the highest quality commercially available (Shimada et al. 1994, Shimada et al. 1999a, b).”
MethodSelf-citation
Biotransformation of Post-Clozapine Antipsychotics
Caccia, S. (2000) · Clinical Pharmacokinetics · doi:10.2165/00003088-200038050-00002 · Cited by 74
Prediction of in Vivo Drug-Drug Interactions between Tolbutamide and Various Sulfonamides in Humans Based on in Vitro Experiments
Komatsu, K., Ito, K., Nakajima, Y., Kanamitsu, S.-I., Imaoka, S., Funae, Y., Green, C. E., Tyson, C. A., Shimada, N., & Sugiyama, Y. (2000) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)15066-0 · Cited by 74
“2 mg of human liver microsomal protein (Shimada et al., 1994).”
Effects of freezing, thawing, and storage of human liver samples on the microsomal contents and activities of cytochrome P450 enzymes.
Yamazaki, H., Inoue, K., Turvy, C. G., et al. (1997) · PubMed · Cited by 74
Self-citation
A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 genein vitro
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Cell based approaches for evaluation of drug-induced liver injury
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Metabolism and Interaction of Bisphenol A in Human Hepatic Cytochrome P450 and Steroidogenic CYP17.
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Sex-related differences in pharmacokinetics and pharmacodynamics of anti-hypertensive drugs
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Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes
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“CYP3A4 is universally expressed in adult human liver accounting for, on average, 29% of the total hepatic CYP (37) and relatively high levels of the protein (f50% of hepatic levels) are also present in the small intestine, playing a significant role in the first pass metabolism of various drugs (38).”
Background
Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers
Ghotbi, R., Gomez, A. V., Milani, L. A., Tybring, G., Syvänen, A., Bertilsson, L., Ingelman‐Sundberg, M., & Aklillu, E. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.4 · Cited by 73
Drug interactions with phytotherapeutics in oncology
Haefeli, W. E., & Carls, A. (2014) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2014.873786 · Cited by 73
“The second most frequently involved isozyme is CYP2D6, which contributes to oxidative metabolism of 25% of drugs [24].”
Background
Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients
Cabrera, S., Santos, D., Valverde, M.-P., et al. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01537-08 · Cited by 73
“Differences in PK due to the CYP2B6 polymorphisms have been reported for several drugs, including EFV, that are mainly metabolized by this isoenzyme (7, 37, 39).”
Background
Environmental phthalate monoesters activate pregnane X receptor-mediated transcription
Hurst, C. H. (2004) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2003.11.028 · Cited by 73
“CYP3A4 is the most abundant P450 form in human liver, but its expression levels can vary approximately 60-fold among individuals (Shimada et al., 1994).”
Background
Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: An interaction study with fluvoxamine and ketoconazole as in vivo inhibitors*
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Age-related modifications in CYP-dependent drug metabolism: role of stress
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“In several studies, no significant modifications of specific CYP isozyme expression patterns were observed in the liver of subjects aged between 12 and 73 years (102, 127, 128).”
Background
CYP3A4 and CYP3A5 Genotyping Recommendations
Pratt, V. M., Cavallari, L. H., Fulmer, M. L., et al. (2023) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2023.06.008 · Cited by 72
Ginkgo biloba: Evaluation of CYP2C9 Drug Interactions In Vitro and In Vivo
Mohutsky, M. A., Anderson, G. D., Miller, J. W., & Elmer, G. W. (2006) · American Journal of Therapeutics · doi:10.1097/01.mjt.0000143695.68285.31 · Cited by 72
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Recombinant CYP3A4*17 Is Defective in Metabolizing the Hypertensive Drug Nifedipine, and the CYP3A4*17 Allele May Occur on the Same Chromosome as CYP3A5*3, Representing a New Putative Defective CYP3A Haplotype
Lee, S., Bell, D. A., Coulter, S. J., Ghanayem, B. I., & Goldstein, J. A. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.078758 · Cited by 73
“Although there are variations in estimates of the relative importance of CYP3A4 and CYP3A5 in the literature (Shimada et al., 1994; Evans and Relling, 1999; Kuehl et al., 2001), these P450s have overlapping substrate specificity (Wrighton et al.”
BackgroundInfluential
STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS
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Involvement of CYP1A2 in mexiletine metabolism
Nakajima, M., Kobayashi, K., Shimada, N., et al. (1998) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1998.00048.x · Cited by 72
Cytochrome P-450 3A and 2D6 Catalyze Ortho Hydroxylation of 4-Hydroxytamoxifen and 3-Hydroxytamoxifen (Droloxifene) Yielding Tamoxifen Catechol: Involvement of Catechols in Covalent Binding to Hepatic Proteins
Dehal, S. S., & Kupfer, D. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)15305-6 · Cited by 71
“Because CYP3A4 is the major isoform in human liver microsomes (Shimada et al., 1994), catechol formation from4-OH-tam would primarily be due to CYP3A4 activity; however, it is conceivable that when 3A4 is limiting by being present at low levels (Table 3) or by being inhibited, then 2D6 would be a…”
Background

Authors: Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., & Guengerich, F. P.
Affiliations: Osaka Prefectural Institute of Public Health (JP)
ORCID: Shimada, T
Yamazaki, H
Guengerich, F P
Venue: The Journal of Pharmacology and Experimental Therapeutics
Publisher: Elsevier BV
Published: 1994-07
Volume: 270
Issue: 1
Pages: 414-423
ISSN: 0022-3565 (ISSN-L)
DOI: 10.1016/s0022-3565(25)22379-5
OpenAlex: W2155268095
Cited by: 2,785
References: 0
Citations by year: 2026: 14 · 2025: 28 · 2024: 24 · 2023: 40 · 2022: 36 · 2021: 55 · 2020: 41 · 2019: 59 · 2018: 52 · 2017: 53 · 2016: 75 · 2015: 81 · 2014: 121 · 2013: 104 · 2012: 118
FWCI: 64.47
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
PubMed (publishedVersion)
PubMed
Funders: National Institutes of Health (5r35ca044353-14)
National Cancer Institute (CA 44353)
National Institute of Environmental Health Sciences (ES00267)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords: cytochrome P450, interindividual variability, liver microsomes, CYP1A2, CYP2A6, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP3A4, monooxygenase activity, procarcinogen metabolism, drug metabolism, sex differences
MeSH terms: Adolescent, Adult, Aged, Aging, Biotransformation, Carcinogens, Child, Cytochrome P-450 Enzyme System, Pharmaceutical Preparations, Female, Humans, Individuality, Infant, Isoenzymes, Japan, Liver, Male, Microsomes, Liver, Middle Aged, Oxidation-Reduction, Sex Factors, Hazardous Substances, White People

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Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians

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