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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Result
Genetic epidemiology of induced CYP3A4 activity
Rahmioğlu, N., Heaton, J. C., Clement, G., et al. (2011) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3283498ecf · Cited by 58
Gene Expression Variability in Human Hepatic Drug Metabolizing Enzymes and Transporters
Yang, L., Price, E. T., Chang, C., Li, Y., Huang, Y. S., Guo, L.-W., Guo, Y., Kaput, J., Shi, L. M., & Ning, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060368 · Cited by 64
“Other studies focusing on interindividual variability of DMET were limited by small sample sizes and/or a focus on a subset of hepatic DMETs [9,11,12,13].”
Background
Potential health benefits of sulforaphane: A review of the experimental, clinical and epidemiological evidences and underlying mechanisms
Elbarbry, F., & Elrody, N. (2011) · Journal of Medicinal Plants Research · doi:10.5897/jmpr.9001033 · Cited by 58
INTERACTION OF BUPRENORPHINE AND ITS METABOLITE NORBUPRENORPHINE WITH CYTOCHROMES P450 IN VITRO
Zhang, W., Ramamoorthy, Y., Tyndale, R. F., et al. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.6.768 · Cited by 58
“1 Abbreviations used are: BUP, buprenorphine; P450, cytochrome P450; Nor-”
Background
Cytochrome P450 Expression and Chemical Metabolic Activity before Full Liver Development in Zebrafish
Nawaji, T., Yamashita, N., Umeda, H., Zhang, S., Mizoguchi, N., Seki, M., Kitazawa, T., & Teraoka, H. (2020) · Pharmaceuticals · doi:10.3390/ph13120456 · Cited by 57
The Effect of microRNAs in the Regulation of Human CYP3A4: a Systematic Study using a Mathematical Model
Wei, Z., Jiang, S., Zhang, Y., Wang, X., Peng, X., Meng, C., Liu, Y., Wang, H., Guo, L., Qin, S., et al. (2014) · Scientific Reports · doi:10.1038/srep04283 · Cited by 57
CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems
Wu, Z., Lee, D., Joo, J., Shin, J., Kang, W., Oh, S., Lee, D. Y., Lee, S., Yea, S. S., Lee, H. S., et al. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00843-13 · Cited by 57
A Theoretical Physiologically‐Based Pharmacokinetic Approach to Ascertain Covariates Explaining the Large Interpatient Variability in Tacrolimus Disposition
Emoto, C., Johnson, T. N., Hahn, D., Christians, U., Alloway, R. R., Vinks, A. A. T. M. M., & Fukuda, T. (2019) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12392 · Cited by 57
“Tacrolimus is a substrate of CYP3A4 and CYP3A5,(5) which are expressed in both small intestine(6) and liver tissue.(7) The fraction of tacrolimus escaping gut wall metabolism (Fg) was estimated to be 0.”
Background
Induction of CYP3A by Ethanol in Multiple In Vitro and In Vivo Models
Feierman, D. E., Melinkov, Z., & Nanji, A. A. (2003) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2003.tb04424.x · Cited by 57
Optimizing Higher Throughput Methods to Assess Drug–Drug Interactions for CYP1A2, CYP2C9, CYP2C19, CYP2D6, rCYP2D6, and CYP3A4 In Vitro Using a Single Point IC50
Gao, F., Johnson, D. L., Ekins, S., et al. (2002) · SLAS DISCOVERY · doi:10.1177/108705710200700410 · Cited by 57
Induction of cytochrome P450-dependent monooxygenase by extracts of the medicinal herbSalvia miltiorrhiza
Lin, Y., Don, M., Kuo, Y.-H., et al. (2006) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp.58.4.0012 · Cited by 57
“CYP1A2, CYP2C and CYP3A constitute about 13%, 20% and 30% of the total human hepatic P450 content, respectively (Shimada et al 1994).”
Background
The Impact of Cytochrome P450 2E1‐Dependent Metabolic Variance on a Risk‐Relevant Pharmacokinetic Outcome in Humans
Lipscomb, J. C., Teuschler, L. K., Swartout, J., Popken, D. A., Cox, T., & Kedderis, G. L. (2003) · Risk Analysis · doi:10.1111/j.0272-4332.2003.00397.x · Cited by 57
“With respect to the distribution of the cytochromes P450 in one preparation of human liver (microsomes), several investigations(17,36,40,41) have revealed quantitative information about the content of these multiple enzyme forms in this preparation, but reveal no direct information on the type of distribution (i.”
Background
Influence of CYP2D6 Genotype on Metoprolol Plasma Concentration and β-Adrenergic Inhibition During Long-Term Treatment
Nozawa, T., Taguchi, M., Tahara, K., et al. (2005) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000184117.76188.68 · Cited by 57
“About half of administered bisoprolol is excreted unchanged in the urine and bisoprolol metabolism is catalyzed by the two CYP isoforms, CYP2D6 and CYP3A4.”
Background
IN VIVO INDUCTION OF HUMAN CYTOCHROME P450 ENZYMES EXPRESSED IN CHIMERIC MICE WITH HUMANIZED LIVER
Katoh, M., Matsui, T., Nakajima, M., Tateno, C., Soeno, Y., Horie, T., Iwasaki, K., Yoshizato, K., & Yokoi, T. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.104.002600 · Cited by 57
“CYP3A4 is the predominant isoform in human liver and small intestine (Shimada et al., 1994; Ding and Kaminsky, 2003) and is responsible for the metabolism of many clinical drugs (Li et al.”
Background
Cytochrome P-450 expression in sudden infant death syndrome
Tréluyer, J., Chéron, G., Sonnier, M., & Cresteil, T. (1996) · Biochemical Pharmacology · doi:10.1016/0006-2952(96)00253-5 · Cited by 57
ROLE OF HUMAN CYTOCHROME P450 (CYP) IN THE METABOLIC ACTIVATION OF NITROSAMINE DERIVATIVES: APPLICATION OF GENETICALLY ENGINEEREDSALMONELLAEXPRESSING HUMAN CYP
Kamataki, T., Fujita, K., Nakayama, K., Yamazaki, Y., Miyamoto, M., & Ariyoshi, N. (2002) · Drug Metabolism Reviews · doi:10.1081/dmr-120005668 · Cited by 58
“For example, the level of CYP2A6 expressed in 1 L of a culture of S. typhimurium YG7108 cells corresponded to that expressed in 135 g of human liver, assuming that 1 g of the human adult liver contained about 0.53 nmol of CYP2A6 protein, as reported by Shimada et al.[25] The expression levels of the OR varied dependin…”
BackgroundInfluential
Characterization of the Rhesus Monkey CYP3A64 Enzyme: Species Comparisons of CYP3A Substrate Specificity and Kinetics Using Baculovirus-Expressed Recombinant Enzymes
Carr, B., Norcross, R., Fang, Y., Lu, P., Rodrigues, A. D., Shou, M., Rushmore, T. H., & Booth-Genthe, C. L. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.009977 · Cited by 58
“These values appear to be underestimated based on literature reports of the abundance of CYP3A proteins in rhesus or in relation to human (Stevens et al., 1993; Shimada et al., 1994).”
Background
Paradisin C: a new CYP3A4 inhibitor from grapefruit juice
Ohta, T., Maruyama, T., Nagahashi, M., Miyamoto, Y., Hosoi, S., Kiuchi, F., Yamazoe, Y., & Tsukamoto, S. (2002) · Tetrahedron · doi:10.1016/s0040-4020(02)00739-1 · Cited by 57
Cytochrome P450 polymorphisms and response to antipsychotic therapy
Scordo, M. G., & Spina, E. (2002) · Pharmacogenomics · doi:10.1517/14622416.3.2.201 · Cited by 57
Inhibition of Human Cytochrome P450‐3A Isoforms by Fluoxetine and Norfluoxetine: In Vitro and In Vivo Studies
Greenblatt, D. J., Moltke, L. L., Schmider, J., Harmatz, J. S., & Shader, R. I. (1996) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1996.tb04252.x · Cited by 57
Simple Voltammetric Determination of Rhodamine B by Using the Glassy Carbon Electrode in Fruit Juice and Preserved Fruit
Yu, L., Mao, Y., & Qu, L. (2013) · Food Analytical Methods · doi:10.1007/s12161-013-9580-1 · Cited by 56
“…to the International Agency for Research on Cancer (IARC): Ingestion, inhalation, and skin contact of the substance may cause acute and chronic poisoning and injury (Merouani et al. 2010; Kornbrust and Barfknecht 1985; IARC 1987; Mirsalis et al. 1989; McGregor et al. 1991; Shimada et al. 1994).”
BackgroundMethod
Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes
Murai, K., Yamazaki, H., Nakagawa, K., et al. (2009) · Xenobiotica · doi:10.3109/00498250903171395 · Cited by 56
“Their relative in vivo contributions, however, are also determined by their relative abundance in the liver, which is higher for CYP3A4 than CYP2A6 (Shimada et al. 1994).”
BackgroundSelf-citation
Herb–drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats
Chien, C.-F., Wu, Y., Lee, W.-C., Lin, L.-C., & Tsai, T. (2010) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2010.01.017 · Cited by 56
CYP2D6-CYP2C9 Protein-Protein Interactions and Isoform-Selective Effects on Substrate Binding and Catalysis
Subramanian, M., Löw, M., Locuson, C. W., et al. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.109.026500 · Cited by 56
“In addition, both apo- and holo-b5 enhanced metabolism by CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 in reconstituted systems (Shimada et al., 1994), suggesting that the effect of these protein-protein interactions of the redox partner with P450 may involve enzyme conformational…”
BackgroundInfluential
Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model
Cubitt, H. E., Yeo, K. R., Howgate, E. M., Rostami‐Hodjegan, A., & Barter, Z. E. (2011) · Xenobiotica · doi:10.3109/00498254.2011.560294 · Cited by 55
“Of the four CYP3A genes identified in human, significant concentrations of protein have been found for CYP3A4 and CYP3A5 (Shimada et al., 1994; Paine et al., 1997; Hustert et al., 2001; Kuehl et al., 2001).”
BackgroundInfluential
Influence of genetic variation inCYP3A4andABCB1on dose decrease or switching during simvastatin and atorvastatin therapy
Becker, M. L., Visser, L. E., van Schaik, R. H. N., Albert Hofman, D., Uitterlinden, A. G., & Stricker, B. H. C. (2009) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.1866 · Cited by 56
“However, in a study on human liver samples no sex related differences in CYP3A4 content and activity were found, and differences may also be attributable to differences in ABCB1 expression between men and women.(16,29) Indeed, ABCB1 expression was reported to be lower in women than in men, leading to increased intrace…”
Autism spectrum disorders may be due to cerebral toxoplasmosis associated with chronic neuroinflammation causing persistent hypercytokinemia that resulted in an increased lipid peroxidation, oxidative stress, and depressed metabolism of endogenous and exogenous substances
PRANDOTA, J. (2009) · Research in Autism · doi:10.1016/j.rasd.2009.09.011 · Cited by 56
Cytochrome P450 and flavin-containing monooxygenase families: age-dependent differences in expression and functional activity
Zane, N. R., Chen, Y., Wang, M. Z., & Thakker, D. R. (2017) · Pediatric Research · doi:10.1038/pr.2017.226 · Cited by 57
“Overall, the CYP3A and CYP2C families account for 60% of hepatic enzymes and metabolize over 70% of drugs currently on the market (1,23).”
Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism
Glaenzel, U., Jin, Y., Nufer, R., Li, W., Schroer, K., Adam-Stitah, S., van Marle, S. P., Legangneux, E., Borell, H., James, A. D., et al. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.117.079574 · Cited by 57
“Enzymes of the CYP3A subfamily are the most abundant CYP enzymes in HLMs, although the levels vary enormously (.10-fold) among individuals, whereas CYP3A5 expression is relatively low in HLMs (10%–30% of human livers) (Shimada et al., 1994; Yeo et al., 2004).”
Background
Effects of cytochrome b5 on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7
Yamaori, S., Yamazaki, H., Suzuki, A., Yamada, A., Tani, H., Kamidate, T., Fujita, K., & Kamataki, T. (2003) · Biochemical Pharmacology · doi:10.1016/j.bcp.2003.08.004 · Cited by 55
Self-citation
Metabolic Regio- and Stereoselectivity of Cytochrome P450 2D6 towards 3,4-Methylenedioxy-N-alkylamphetamines: in Silico Predictions and Experimental Validation
Keizers, P. H. J., de Graaf, C., de Kanter, F. J. J., Oostenbrink, C., Feenstra, K. A., Commandeur, J. N. M., & Vermeulen, N. P. E. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050338+ · Cited by 57
Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment
Turesky, R. J. (2004) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200400076 · Cited by 56

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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