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
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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CYP3A4 is the most abundant CYP expressed in the adult liver.
“CYP3A4 is the most abundant CYP expressed in the adult liver [121,122]”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [122]
CYP3A4 makes the major contribution to steroid metabolism.
“makes the major contribution to steroid metabolism.”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [122]
CYP3A4 is the most abundant P450 in the liver and predominantly, though not exclusively, catalyses the 6β-hydroxylation of T and the 16α- and 7α-hydroxylation of DHEA.
“CYP3A4 is the most abundant P450 in the liver (∼30%) (Shimada et al., 1994) and predominantly, though not exclusively, catalyses the 6β-hydroxylation of T and the 16α- and 7α-hydroxylation of DHEA (Niwa et al., 2015).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Shimada et al., 1994
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“differences (Shimada et al., 1994; Kim et al., 1997) in CYP2B6 expression have been recognized.”
Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized?
Lin, J. H., Chiba, M., & Baillie, T. A. (1999) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01402-9 · Cited by 354 · see citing works
“The average total cytochrome P-450 content in human intestine, about 20 pmol/mg microsomal protein, was found to be much lower than that in the liver (300 pmol/mg microsomal protein) (Peters and Kremers, 1989; Shimada et al., 1994).”
Activation and detoxication of aflatoxin B1
Guengerich, F. P., Johnson, W. W., Shimada, T., et al. (1998) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(97)00289-3 · Cited by 345 · see citing works
Self-citationBièche, I., Narjoz, C., Asselah, T., Vacher, S., Marcellin, P., Lidereau, R., Beaune, P. H., & de Waziers, I. (2007) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32810f2e58 · Cited by 339 · see citing works
CYP2C9 allelic variants: ethnic distribution and functional significance
Xie, H., Prasad, H. C., Kim, R. B., et al. (2002) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00076-5 · Cited by 339 · see citing works
Eagling, V. A., Tjia, J. F., & Back, D. J. (1998) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1998.00679.x · Cited by 337 · see citing works
Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species
Guengerich, F. P. (1997) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(97)00068-9 · Cited by 329 · see citing works
Self-citationOntogeny of Hepatic and Renal Systemic Clearance Pathways in Infants
Alcorn, J., & McNamara, P. J. (2002) · Clinical Pharmacokinetics · doi:10.2165/00003088-200241120-00003 · Cited by 334 · see citing works
Varma, M. V. S., Obach, R. S., Rotter, C. J., Miller, H., Chang, G., Steyn, S. J., El‐Kattan, A. F., & Troutman, M. D. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901371v · Cited by 332 · see citing works
Yuan, R., Madani, S., Wei, X., et al. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.12.1311 · Cited by 327 · see citing works
“(Shimada et al., 1994), it is responsible for metabolizing drugs in a”
BackgroundInfluentialDevelopmental Expression of Human Hepatic CYP2C9 and CYP2C19
Koukouritaki, S. B., Manro, J. R., Marsh, S. A., Stevens, J. C., Rettie, A. E., McCarver, D. G., & Hines, R. N. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.060137 · Cited by 327 · see citing works
“…content in the oldest age bracket (>5 mos through 18 yrs; N = 79; median = 5.0 yrs) of 18.0 ± 6.0 pmol/mg microsomal protein is significantly less than the total CYP2C specific content of 60 ± 27 pmol/mg protein (N=60; median age=54.5 yrs) reported by Shimada et al. (1994) (ANOVA, p < 0.001).”
BackgroundMethodInfluentialTranscriptional Control of Intestinal Cytochrome P-4503A by 1α,25-Dihydroxy Vitamin D3
Thummel, K. E., Brimer, C., Yasuda, K., Thottassery, J. V., Senn, T., Lin, Y., Ishizuka, H., Kharasch, E. D., Schuetz, J. D., & Schuetz, E. G. (2001) · Molecular Pharmacology · doi:10.1124/mol.60.6.1399 · Cited by 325 · see citing works
Mechanisms of Clinically Relevant Drug Interactions Associated with Tacrolimus
Christians, U., Jacobsen, W., Benet, L. Z., & Lampen, A. (2002) · Clinical Pharmacokinetics · doi:10.2165/00003088-200241110-00003 · Cited by 324 · see citing works
Anderson, G. D. (2005) · Journal of Women s Health · doi:10.1089/jwh.2005.14.19 · Cited by 320 · see citing works
Roy, P., Yu, L. J., Crespi, C. L., & Waxman, D. J. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)15302-0 · Cited by 321 · see citing works
“However, the catalytic contribution of 3A5 and 3A7 to adult human liver oxazaphosphorine activation is likely minor compared with 3A4, in view of the absence or low level of 3A5 in a majority of human livers (Shimada et al., 1994) and the preferential expression of 3A7 in fetal liver tissue (Schuetz et al.”
BackgroundResultInfluentialEnzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction
Thummel, K. E. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00039-2 · Cited by 318 · see citing works
Induction of CYP2C genes in human hepatocytes in primary culture.
Gerbal‐Chaloin, S., Pascussi, J., Pichard‐Garcia, L., Daujat‐Chavanieu, M., Waechter, F., Fabre, J.-M., Carrère, N., & Maurel, P. (2001) · PubMed · Cited by 318 · see citing works
Common allelic variants of cytochrome P4503A4 and their prevalence in different populations
Lamba, J. K., Lin, Y. S., Thummel, K. E., et al. (2002) · Pharmacogenetics · doi:10.1097/00008571-200203000-00006 · Cited by 316 · see citing works
Pharmacogenetics of Warfarin Elimination and Its Clinical Implications
Takahashi, H., & Echizen, H. (2001) · Clinical Pharmacokinetics · doi:10.2165/00003088-200140080-00003 · Cited by 312 · see citing works
Yamazaki, H., & Shimada, T. (1997) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1997.0302 · Cited by 310 · see citing works
Self-citationHuman Drug Metabolism and the Cytochromes P450: Application and Relevance of In Vitro Models
Venkatakrishnan, K., Moltke, L. L., & Greenblatt, D. J. (2001) · The Journal of Clinical Pharmacology · doi:10.1177/00912700122012724 · Cited by 309 · see citing works
“CYP2A6 may participate in procarcinogen activation but has a relatively minor role in drug biotransformation and accounts for only approximately 4% of total immunoquantified human hepatic CYP.7 CYP2A6 is a coumarin 7-hydroxylase, partici- pates in nicotine metabolism, and contributes to the reductive metabolism of the…”
BackgroundInfluentialChauret, N., Gauthier, A., & Nicoll‐Griffith, D. A. (1998) · PubMed · Cited by 309 · see citing works
- Authors
- Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., & Guengerich, F. P.
- Affiliations
- Osaka Prefectural Institute of Public Health (JP)
- 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)
- 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
- 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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