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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Background
Topics on Drug Metabolism
Paxton, J. W. (2012) · InTech eBooks · doi:10.5772/1180 · Cited by 90
Molecular modelling of CYP3A4 from an alignment with CYP102: Identification of key interactions between putative active site residues and CYP3A-specific chemicals
Lewis, D. F. V., Eddershaw, P. J., Goldfarb, P. S., & Tarbit, M. H. (1996) · Xenobiotica · doi:10.3109/00498259609167423 · Cited by 89
CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations
Balram, C., Zhou, Q. S., Cheung, Y. B., & Lee, E. J. D. (2003) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-003-0594-2 · Cited by 87
Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation
Palovaara, S. (2003) · Clinical Pharmacology & Therapeutics · doi:10.1016/s0009-9236(03)00202-9 · Cited by 87
“Until recently, the role of the CYP2B6 isozyme in hepatic drug clearance has been considered rather insignificant on the basis of earlier studies estimating a low expression of CYP2B6 protein in human liver.(18,19) However, studies with more specific techniques suggest a higher abundance of CYP2B6 in human liver with…”
Background
Molecular basis for rhythmic expression of CYP3A4 in serum-shocked HepG2 cells
Takiguchi, T., Tomita, M., Matsunaga, N., Nakagawa, H., Koyanagi, S., & Ohdo, S. (2007) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3282f12a61 · Cited by 87
In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver
Katoh, M., Sawada, T., Soeno, Y., Nakajima, M., Tateno, C., Yoshizato, K., & Yokoi, T. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20783 · Cited by 86
Developmental Changes in the Expression and Function of Cytochrome P450 3A Isoforms: Evidence from In Vitro and In Vivo Investigations
Ince, I., Knibbe, C. A. J., Danhof, M., & de Wildt, S. N. (2013) · Clinical Pharmacokinetics · doi:10.1007/s40262-013-0041-1 · Cited by 88
“Midazolam is extensively metabolized by CYP3A4 and CYP3A5 to 1-OH-midazolam, 4-OH-midazolam, and 1,4-OH-midazolam, and meets most of the criteria for an ideal in vivo CYP3A probe for clinical studies [76].”
Background
Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping*
Kashuba, A. D. M., Bertino, J., KEARNS, G., Leeder, J. S., James, A. W., Gotschall, R. R., & Nafziger, A. N. (1998) · Clinical Pharmacology & Therapeutics · doi:10.1016/s0009-9236(98)90105-9 · Cited by 85
“To address these discrepancies, we conducted a study with the following specific aims: (1) to determine whether the activities of CYPlA2, NAT2, and xanthine oxidase as assessed with urinary metabolite ratios for caffeine differ during the midfollicular and midluteal phases of the menstrual cycle, (2) to determine whet…”
Method
Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans
Shon, J., Yoon, Y.-R., Kim, K., et al. (2002) · Pharmacogenetics · doi:10.1097/00008571-200203000-00005 · Cited by 87
Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization
Chiou, W. L., Jeong, H. Y., Wu, T. C., et al. (2001) · Clinical Pharmacology & Therapeutics · doi:10.1016/s0009-9236(01)45600-1 · Cited by 87
Six Novel Nonsynonymous CYP1A2 Gene Polymorphisms: Catalytic Activities of the Naturally Occurring Variant Enzymes
Murayama, N., Soyama, A., Saito, Y., Nakajima, Y., Komamura, K., Ueno, K., Kamakura, S., Kitakaze, M., Kimura, H., Goto, Y., et al. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.055798 · Cited by 86
“Interindividual difference in CYP1A2 protein was reported to be up to 60-fold (Shimada et al., 1994).”
Background
Comparison of CYP2D6 Content and Metoprolol Oxidation Between Microsomes Isolated from Human Livers and Small Intestines
Madani, S., Paine, M. F., Lewis, L., Thummel, K. E., & Shen, D. D. (1999) · Pharmaceutical Research · doi:10.1023/a:1018989211864 · Cited by 85
CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia
Inomata, S., NAGASHIMA, A., Itagaki, F., Homma, M., Nishimura, M., Osaka, Y., OKUYAMA, K., Tanaka, E., Nakamura, T. K., & Kohda, Y. (2005) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2005.08.020 · Cited by 86
“In addition, there is nterindividual variability in CYP3A4 activity.(7,8) BeFig 1.”
Background
CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population
Mirghani, R. A., Sayi, J., Aklillu, E., Allqvist, A., Jande, M. B., Wennerholm, A., Eriksen, J., Herben, V. M. M., Jones, B., Gustafsson, L. L., et al. (2006) · Pharmacogenetics and Genomics · doi:10.1097/01.fpc.0000230411.89973.1b · Cited by 85
Dose‐dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL
Martin‐Facklam, M., Burhenne, J., Ding, R., et al. (2002) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.2002.01595.x · Cited by 86
Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol
Yamamoto, N., Tamura, T., Murakami, H., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.11.036 · Cited by 86
Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19
Yu, K. (2001) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2001.114231 · Cited by 86
Induction of Human CYP2A6 Is Mediated by the Pregnane X Receptor with Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α
Itoh, M., Nakajima, M., Higashi, E., Yoshida, R., Nagata, K., Yamazoe, Y., & Yokoi, T. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.107573 · Cited by 85
“Large interindividual variability exists in the enzymatic activity and protein level of CYP2A6 in human livers (Shimada et al., 1994).”
Background
The Inhibitory Effects of Herbal Components on CYP2C9 and CYP3A4 Catalytic Activities in Human Liver Microsomes
He, N., & Edeki, T. I. (2004) · American Journal of Therapeutics · doi:10.1097/00045391-200405000-00009 · Cited by 85
“The CYP2C subfamily is second in quantity only to the CYP3A subfamily.(7) CYP2C9 metabolizes many clinically relevant substrates, including the oral anticoagulants warfarin and acenocoumarol, the oral hypoglycemics tolbutamide and glipizide, the anticonvulsant phenytoin, the loop diuretic torsemide, the angiotensin II…”
Background
Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR
Gay, S. C., Roberts, A. G., & Halpert, J. R. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.10.229 · Cited by 86
“Substrate specificity—CYP2E1 comprises over 50% of hepatic P450 mRNA [61] and 7% of hepatic P450 protein content [62].”
Background
The CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes
Okubo, M., Murayama, N., Shimizu, M., Shimada, T., Guengerich, F. P., & Yamazaki, H. (2013) · The Journal of Toxicological Sciences · doi:10.2131/jts.38.349 · Cited by 85
Self-citation
The influence of the incorporation of cholesterol and water on the particle size, bilayer thickness, melting behavior, and relative sucrose ester composition of reversed vesicles
Mollee, H., Steenvoorden, D. P. T., de Vringer, T., & Crommelin, D. J. A. (2001) · Journal of Pharmaceutical Sciences · doi:10.1002/1520-6017(200105)90:5 · Cited by 7
In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine
Lobo, E. D., Bergstrom, R. F., Reddy, S. R., et al. (2008) · Clinical Pharmacokinetics · doi:10.2165/00003088-200847030-00005 · Cited by 85
Significantly Altered Systemic Exposure to Atorvastatin Acid Following Gastric Bypass Surgery in Morbidly Obese Patients
Skottheim, I. B., Stormark, K., Christensen, H., Jakobsen, G. S., Hjelmesaeth, J. S., Jenssen, T. G., Reubsaet, L., Sandbu, R., & Åsberg, A. (2009) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.82 · Cited by 87
Reappraisal of Human CYP Isoforms Involved in Imipramine N-Demethylation and 2-Hydroxylation: A Study Using Microsomes Obtained from Putative Extensive and Poor Metabolizers of S-Mephenytoin and Eleven Recombinant Human CYPs
Koyama, E., Chiba, K., Tani, M., & Ishizaki, T. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36731-x · Cited by 84
CYP1A2 Activity as Measured by a Caffeine Test Predicts Clozapine and Active Metabolite Norclozapine Steady-State Concentration in Patients With Schizophrenia
Özdemir, V., KALOW, W., Posner, P., Collins, E. J., Kennedy, J. L., Tang, B.-K., Albers, L. J., Reist, C., Roy, R., Walkes, W., et al. (2001) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200108000-00007 · Cited by 85
Molecular modelling of CYP1A subfamily members based on an alignment with CYP102: rationalization of CYP1A substrate specificity in terms of active site amino acid residues
Lewis, D. F. V., & Lake, B. G. (1996) · Xenobiotica · doi:10.3109/00498259609046745 · Cited by 85
CYP2D plays a major role in berberine metabolism in liver of mice and humans
Guo, Y., Li, F., Ma, X., Cheng, X., Zhou, H., & Klaassen, C. D. (2011) · Xenobiotica · doi:10.3109/00498254.2011.597456 · Cited by 86
“CYP3A4 accounts for 30% of CYPs in liver (Shimada et al., 1994) and 80% of the CYPs in small intestine (Watkins et al.”
The NTCP‐inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics
Blank, A., Eidam, A., Haag, M., Hohmann, N., Burhenne, J., Schwab, M. G., van de Graaf, S. F. J., Meyer, M. R., Maurer, H., Meier, K., et al. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.744 · Cited by 84
“In addition, potential perpetrator characteristics of a drug on major metabolic pathways, such as the CYP3A4 pathway, are of relevance.(16) We designed and conducted an open label, prospective trial assessing the influence of myrcludex B on plasma bile acids and”
Method
Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport
Katoh, M., Nakajima, M., Yamazaki, H., et al. (2001) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(00)00215-3 · Cited by 84
Self-citation
Pharmacogenetics
Wolf, C. R., & Smith, G. C. (1999) · British Medical Bulletin · doi:10.1258/0007142991902439 · Cited by 84
Toxicological Implications of Modulation of Gene Expression by MicroRNAs
Yokoi, T., & Nakajima, M. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr168 · Cited by 85
Epoxyeicosatrienoic acids: formation, metabolism and potential role in tissue physiology and pathophysiology
Kaspera, R., & Totah, R. A. (2009) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250902932923 · Cited by 83
“CYP2Cs and also CYP2J2 are strongly expressed on both the mRNA and protein levels (Table 1) [33] and metabolize arachidonic acid [34-36].”
Background
Gender Differences in P-Glycoprotein Expression and Function: Effects on Drug Disposition and Outcome
Bebawy, M., & Chetty, M. (2009) · Current Drug Metabolism · doi:10.2174/138920009788498996 · Cited by 83

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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