Article

Shimada, T., Yamazake, H., Mimura, M., Inui, Y. & Guengerich, F.P. 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. J. Pharmacol. Exp. Ther. 270, 414−423

Osaka Prefectural Institute of Public Health, Japan.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 07/1994; 270(1):414-23.
Source: PubMed

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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    • "The proportion of each form of CYP in human liver microsomes is reported to be 4% for CYP2A6 and 30% for CYP3A4/5 [47]. The molar ratio of OR to CYP in human liver microsomes depends on the amount of each form of CYP. "

    Full-text · Dataset · Sep 2015
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    • "The proportion of each form of CYP in human liver microsomes is reported to be 4% for CYP2A6 and 30% for CYP3A4/5 [47]. The molar ratio of OR to CYP in human liver microsomes depends on the amount of each form of CYP. "

    Full-text · Dataset · Sep 2015
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    • "Where metabolic clearance is defined largely by a single cytochrome P450, this phenomenon can result in pediatric patients who present as phenotypically similar but actually have disparate genotypes that have yet to be realized. Although CYP2D6 accounts for 2% or less of the hepatic cytochrome P450 content (Shimada et al., 1994), this enzyme is responsible for the oxidative metabolism of approximately 12% of clinically relevant drugs (Williams et al., 2004). Furthermore, the CYP2D6 locus exhibits a high degree of genetic polymorphism that clearly has been linked to the variable pharmacological response to a variety of analgesic, cardiovascular, and antidepressant drugs (Heim and Meyer, 1992; Eichelbaum et al., 1997; Flores and Mogil, 2001). "

    Full-text · Dataset · Sep 2015
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