MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by NORDQVIST, M.
Right arrow Articles by JERINA, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by NORDQVIST, M.
Right arrow Articles by JERINA, D. M.

Molecular Pharmacology, Vol 19, 168-178, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Metabolism of Chrysene and Phenanthrene to Bay-Region Diol Epoxides by Rat Liver Enzymes

M. NORDQVIST 1, D. R. THAKKER 1, K. P. VYAS 1, H. YAGI 1, W. LEVIN 1, D. E. RYAN 1, P. E. THOMAS 1, A. H. CONNEY 1, and D. M. JERINA 1

1 Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20205, and Department of Biochemistry and Drug Metabolism, Hoffman-La Roche Inc., Nutley, New Jersey 07110

Liver microsomal metabolism of the weak carcinogen chrysene and the noncarcinogen phenanthrene are compared. In general, chrysene is a rather poor substrate whereas phenanthrene is a relatively good substrate for the cytochrome P-450-dependent monooxygenase system. With microsomes from 3-methylcholanthrene-treated rats, phenanthrene was metabolized at a rate of 7.6 nmoles/min/nmole of cytochrome P-450 as compared with a rate of only 1.5 with chrysene as substrate. Dihydrodiols were major metabolites for both substrates, accounting for 92%-96% of the metabolism of phenanthrene and 65%-76% of the metabolism of chrysene with microsomes from control and treated rats. The K-region 9,10-dihydrodiol is the major metabolite of phenanthrene, whereas the benzo-ring 1,2- and 3,4-dihydrodiols dominate the metabolism of chrysene from which very little K-region dihydrodiol was formed. For both hydrocarbons, microsomes from 3-methylcholanthrene-treated rats produced the (-)-[1R,2R]-dihydrodiol, which has a bay-region double bond, with ge80% enantiomeric purity. With microsomes from phenobarbital-treated rats, the chrysene 1,2-dihydrodiol was only 10% enantiomerically pure. The (-)-[3R,4R]-dihydrodiols were the major enantiomers of phenanthrene and chrysene, whereas the (-)-[9S,1OS]-dihydriol predominated at the K-region of phenanthrene. Metabolism of the metabolically formed (-)-[1R,2R]-dihydrodiols of phenanthrene and chrysene by microsomes from 3-methylcholanthrene-treated rats resulted in the predominant formation in each case of a bay-region 1,2-diol-3,4-epoxide in which the benzylic hydroxyl group and oxirane oxygen are trans to each other (isomer-2). The respective 1,2-dihydrodiols were metabolized at the same rate as was chrysene. Thus, as had previously been observed for the metabolism of benzo[a]pyrene and benzo[a]anthracene, liver microsomal enzymes display high stereoselectivity in their formation of predominantly one of four possible stereoisomers of their respective bay-region diol epoxides. These diol epoxides from the four hydrocarbons are superimposable when their bay-regions are aligned.

Submitted on July 14, 1980
Accepted on September 3, 1980




This article has been cited by other articles:


Home page
 CarcinogenesisHome page
S. S. Hecht, P. W. Villalta, and J.B. Hochalter
Analysis of phenanthrene diol epoxide mercapturic acid detoxification products in human urine: relevance to molecular epidemiology studies of glutathione S-transferase polymorphisms
Carcinogenesis, May 1, 2008; 29(5): 937 - 943.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
B. Pesch, M. Kappler, K. Straif, B. Marczynski, R. Preuss, B. Rossbach, H.-P. Rihs, T. Weiss, S. Rabstein, C. Pierl, et al.
Dose-Response Modeling of Occupational Exposure to Polycyclic Aromatic Hydrocarbons with Biomarkers of Exposure and Effect
Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1863 - 1873.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
N. W. Shappell, U. Carlino-MacDonald, S. Amin, S. Kumar, and H. C. Sikka
Comparative Metabolism of Chrysene and 5-Methylchrysene by Rat and Rainbow Trout Liver Microsomes
Toxicol. Sci., April 1, 2003; 72(2): 260 - 266.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
J. Pangrekar, P. L. Kole, S. A. Honey, S. Kumar, and H. C. Sikka
Metabolism of Chrysene by Brown Bullhead Liver Microsomes
Toxicol. Sci., January 1, 2003; 71(1): 67 - 73.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
R. L. Chang, A. W. Wood, S. Kumar, R. E. Lehr, N. Shirai, D. M. Jerina, and A. H. Conney
Tumorigenicity of four optically active bay-region 3,4-diol 1,2-epoxides and other derivatives of the nitrogen heterocycle dibenz[c,h]acridine on mouse skin and in newborn mice
Carcinogenesis, November 1, 2000; 21(11): 1997 - 2003.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics