Induction of rat cytochrome P-450 3 and its mRNA by 3,4,5,3',4',5'- hexachlorobiphenyl

HN Yeowell, DJ Waxman, GA LeBlanc, P Linko and JA Goldstein

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

Rat cytochrome P-450 3 (P-450 3) is a constitutive hepatic steroid hormone 7 alpha-hydroxylase which is relatively unresponsive to a number of monooxygenase-inducing agents. The present study demonstrates that a polyhalogenated aromatic hydrocarbon inducer, 3,4,5,3',4',5'- hexachlorobiphenyl (HCB), induces P-450 3 in livers of adult male rats, and that the increase is the result of an increase in the mRNA for this enzyme. Cytochrome P-450 3 and its mRNA were increased more slowly and to a lesser extent than cytochrome P-450c (P-450c) and its mRNA, indicating that these enzymes are not regulated coordinately in liver. The maximum increase in P-450 3 and P-450 3-dependent androstenedione 7 alpha-hydroxylase activity (2- to 3-fold) occurred 7 days after administration of HCB, in contrast to the increase in P-450c (greater than 200-fold) which was maximal by 3-5 days. The rate of induction of P-450 3 mRNA was also slower [maximum increase (9-fold) at 5 days after HCB administration] than that of P-450c mRNA [maximum increase (30- fold) at 2-3 days]. Moreover, a higher dose of HCB was required to produce maximum induction of P-450 3 (50 mg/kg) than that required to produce maximum induction of P-450c (10 mg/kg). P-450 3 was not detected on Western blots of lung, kidney, or prostate microsomes isolated from control or HCB-treated rats (less than or equal to 2% of that found in livers of HCB-treated rats). Moreover, P-450 3-dependent steroid 7 alpha-hydroxylase activity was not detected in these extrahepatic tissues of control or HCB-treated rats (less than or equal to 1% of that found in the corresponding liver microsomes of untreated or HCB-treated rats). In contrast, P-450c was increased dramatically by HCB in lung, kidney, and prostate tissues, indicating differential expression of P-450c and P-450 3 in extrahepatic tissues.

Volume 33, Issue 3, pp. 272-278, 03/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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