Suppression of the constitutive, male-specific rat hepatic cytochrome P- 450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl and 3- methylcholanthrene

HN Yeowell, DJ Waxman, A Wadhera and JA Goldstein

National Institute of Environmental Health Sciences, Laboratory of Biochemical Risk Analysis, Research Triangle Park, North Carolina 27709.

Rat liver cytochrome P-450 2c (P-450 2c) is a constitutive, male- specific enzyme that oxidatively metabolizes both steroid hormones and liphophilic foreign compounds. Exposure of adult male rats to certain xenobiotics can lead to a decrease in the expression of hepatic P-450 2c. The present studies were undertaken to examine the mechanism of this decrease. Treatment of adult male rats with 3-methylcholanthrene (3-MC) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) (two compounds known to induce P-450c and P-450d as a consequence of their interaction with the aromatic hydrocarbon receptor) decreased hepatic content of P-450 2c and its associated steroid hormone 2 alpha- and 16 alpha-hydroxylase activities. Moreover, the present studies demonstrate that decreases in hepatic content of P-450 2c mRNA (determined by electrophoretic analysis of immunoprecipitated translational products) fully account for the effects of 3-MC and HCB on P-450 2c. HCB (50 mg/kg) produced the most striking decrease in P-450 2c and its mRNA, virtually eliminating their expression in hepatic tissue. The time course and dose-response for the decrease in P-450 2c and its mRNA differed markedly from that for induction of P-450c, indicating that the effects of HCB on the two proteins may involve different mechanisms. Additional experiments demonstrated that the sex difference in hepatic expression of P-450 2c is the result of a greater than 5-fold higher content of P- 450 2c mRNA in male as compared to female rats. HCB decreased serum testosterone levels by greater than 98% at 5 days in adult male rats. However, the decrease in P-450 2c and serum testosterone levels was not accompanied by an increase in serum estradiol levels or induction of the female-specific enzyme P-450 2d. The present findings clearly establish that the decrease in P-450 2c produced by administration of HCB and 3-MC is the result of a decrease in the hepatic content of P- 450 2c mRNA. These xenobiotics may decrease transcription of the mRNA for P-450 2c as a consequence of binding to the aromatic hydrocarbon receptor, or, alternatively, may interfere with the hormonal regulation of the mRNA for this male-specific P-450 enzyme.

Volume 32, Issue 3, pp. 340-347, 09/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				D. S. Riddick, C. Lee, A. Bhathena, Y. E. Timsit, P.-Y. Cheng, E. T. Morgan, R. A. Prough, S. L. Ripp, K. K. M. Miller, A. Jahan, et al. TRANSCRIPTIONAL SUPPRESSION OF CYTOCHROME P450 GENES BY ENDOGENOUS AND EXOGENOUS CHEMICALS Drug Metab. Dispos., April 1, 2004; 32(4): 367 - 375. [Abstract] [Full Text] [PDF]

				A. Bhathena, C. Lee, and D. S. Riddick Suppression of Cytochrome P450 2C11 by Aromatic Hydrocarbons: Mechanistic Insights from Studies of the 5'-Flanking Region of the CYP2C11 Gene Drug Metab. Dispos., December 1, 2002; 30(12): 1385 - 1392. [Abstract] [Full Text] [PDF]

				Y. E. Timsit and D. S. Riddick Stimulation of Hepatic Signal Transducer and Activator of Transcription 5b by GH Is Not Altered by 3-Methylcholanthrene Endocrinology, September 1, 2002; 143(9): 3284 - 3294. [Abstract] [Full Text] [PDF]

				H. Lilienthal, A. Fastabend, J. Hany, H. Kaya, A. Roth-Harer, L. Dunemann, and G. Winneke Reduced Levels of 1,25-Dihydroxyvitamin D3 in Rat Dams and Offspring after Exposure to a Reconstituted PCB Mixture Toxicol. Sci., October 1, 2000; 57(2): 292 - 301. [Abstract] [Full Text] [PDF]

				S. A. Andric, T. S. Kostic, S. S. Stojilkovic, and R. Z. Kovacevic Inhibition of Rat Testicular Androgenesis by a Polychlorinated Biphenyl Mixture Aroclor 1248 Biol Reprod, June 1, 2000; 62(6): 1882 - 1888. [Abstract] [Full Text]