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Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450.
Arch Biochem Biophys. 1996 Apr 01; 328(1):201-7.AB

Abstract

The metabolic activation of the potent carcinogen dibenzo[a,h]anthracene (DB[a,h]A) was investigated with recombinant human cytochrome P450 enzymes 1A2, 2B6, 2C8, 2C9, 2E1, 3A3, 3A4, and 3A5 expressed in hepatoma G2 cells and with 14 different human liver microsomes. Three dihydrodiols, three phenols, and one diphenol were formed and separated by high-performance liquid chromatography and identified by UV absorption and mass spectra. Of all P450s tested, 1A2 and 2C9 were the most active and 2B6 was moderately active in the rate of total DB[a,h]A metabolism (2.5- to 12-fold greater activity than that for other P450s). The trans-3,4-dihydrodiol, generally recognized as a precursor of the ultimate carcinogenic 3,4-diol-1,2-epoxides, was produced most actively by 2C9, then 1A2 and 2B6. The values of enzymatic kinetics (K(m) and V(max)) indicated that 2C9 had the highest catalytic efficiency (V(max)/K(m) = 9.7) in the formation of 3,4-dihydrodiol, in contrast to 1A2 (5.9) and 2B6 (4.4). 1A2 had the highest activity toward production of the 1,2-dihydrodiol, which is considered to be a weakly carcinogenic metabolite. Although specific activities of human liver microsomes in overall metabolism of DB[a,h]A markedly differed between individuals, metabolic patterns were observed similar to that generated from 1A2. Since human 1A1, a predominant enzyme for metabolism of polycyclic aromatic hydrocarbons, is not significantly expressed in the liver, hepatic microsomal 2C9, 1A2, and 2B6 all probably contribute to the metabolic activation of DB[a,h]A.

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Authors+Show Affiliations

Shou M
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Krausz KW
No affiliation info available
Gonzalez FJ
No affiliation info available
Gelboin HV
No affiliation info available

MeSH

Benz(a)AnthracenesBiotransformationCarcinogensCytochrome P-450 Enzyme SystemHumansIsoenzymesKineticsMicrosomes, LiverRecombinant ProteinsSubstrate Specificity

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

8638931

Citation

Shou, M, et al. "Metabolic Activation of the Potent Carcinogen Dibenzo[a,h]anthracene By cDNA-expressed Human Cytochromes P450." Archives of Biochemistry and Biophysics, vol. 328, no. 1, 1996, pp. 201-7.
Shou M, Krausz KW, Gonzalez FJ, et al. Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450. Arch Biochem Biophys. 1996;328(1):201-7.
Shou, M., Krausz, K. W., Gonzalez, F. J., & Gelboin, H. V. (1996). Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450. Archives of Biochemistry and Biophysics, 328(1), 201-7.
Shou M, et al. Metabolic Activation of the Potent Carcinogen Dibenzo[a,h]anthracene By cDNA-expressed Human Cytochromes P450. Arch Biochem Biophys. 1996 Apr 1;328(1):201-7. PubMed PMID: 8638931.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450. AU - Shou,M, AU - Krausz,K W, AU - Gonzalez,F J, AU - Gelboin,H V, PY - 1996/4/1/pubmed PY - 1996/4/1/medline PY - 1996/4/1/entrez SP - 201 EP - 7 JF - Archives of biochemistry and biophysics JO - Arch Biochem Biophys VL - 328 IS - 1 N2 - The metabolic activation of the potent carcinogen dibenzo[a,h]anthracene (DB[a,h]A) was investigated with recombinant human cytochrome P450 enzymes 1A2, 2B6, 2C8, 2C9, 2E1, 3A3, 3A4, and 3A5 expressed in hepatoma G2 cells and with 14 different human liver microsomes. Three dihydrodiols, three phenols, and one diphenol were formed and separated by high-performance liquid chromatography and identified by UV absorption and mass spectra. Of all P450s tested, 1A2 and 2C9 were the most active and 2B6 was moderately active in the rate of total DB[a,h]A metabolism (2.5- to 12-fold greater activity than that for other P450s). The trans-3,4-dihydrodiol, generally recognized as a precursor of the ultimate carcinogenic 3,4-diol-1,2-epoxides, was produced most actively by 2C9, then 1A2 and 2B6. The values of enzymatic kinetics (K(m) and V(max)) indicated that 2C9 had the highest catalytic efficiency (V(max)/K(m) = 9.7) in the formation of 3,4-dihydrodiol, in contrast to 1A2 (5.9) and 2B6 (4.4). 1A2 had the highest activity toward production of the 1,2-dihydrodiol, which is considered to be a weakly carcinogenic metabolite. Although specific activities of human liver microsomes in overall metabolism of DB[a,h]A markedly differed between individuals, metabolic patterns were observed similar to that generated from 1A2. Since human 1A1, a predominant enzyme for metabolism of polycyclic aromatic hydrocarbons, is not significantly expressed in the liver, hepatic microsomal 2C9, 1A2, and 2B6 all probably contribute to the metabolic activation of DB[a,h]A. SN - 0003-9861 UR - https://www.unboundmedicine.com/medline/citation/8638931/Metabolic_activation_of_the_potent_carcinogen_dibenzo[ah]anthracene_by_cDNA_expressed_human_cytochromes_P450_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0003-9861(96)90161-7 DB - PRIME DP - Unbound Medicine ER -