UNIQUE INDUCTION OF CYTOCHROME P-450 ISOZYMES IN RAT LIVER MICROSOMES BY TREATMENT WITH 3,4,5,3', 4'-PENTACHLOROBIPHENYL AND ITS EFFECT ON TESTOSTERONE METABOLISM

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Pretreatment of male Wistar rats wuth 3,4,5,3', 4'-pentachlorobiphenyl (PenCB), a potent 3-methylcholanchrene-type inducer, increased selectively 7α-but strongly repressed 2α-, 6β-and 16α-hydroxylations of testosterone in the liver microsomes. To understand this unique phenomenon, the testosterone metabolism by three isozymes (P-452,P-448 L and P-448 H) of cytochrome P-450 purified from Wistar rats treated with PenCB was studied in a reconstituted system. For comparison 4 other iozymes (P-451 I, P-451 II, P-450 II and P-450 III) of cytochrome P-450 from untreated and phenobarbital-treated rats were also studied. In addition, the contribution of cytochrome P-450's to testosterone hydroxylation was ecamined by an immune complex inhibition of the activity and by a determination of the individual cytochrome P-450 in microsomes using antibodies. In the reconstituted system, 7α-hydroxylation of testosterone was catalyzed almost exclusively by P-452,with the exception of P-451 I. On the other hand, the 6β- hydroxylation was catalyzed by most of the cytochrome P-450's tested at considerably lower rates. Among the seven forms, P451 II was the most effective catalyst for 2α- and 16α-hydroxylations, with equally high turnover numbers, while other forms showed only low or no activity for either or both hydroxylations. The microsomal activity of 7α- hydroxylation in PenCB-treated rats was inhibited almost completely by anti-P-452. A partial inhibition of the 16α-hydroxylation was achieved by anti-P-451 II and anti-P-452 while the 6β-hydroxylation was insensitive to anti-P-451 II but slightly sensitive to anti-P-452. The activity of 2α-hydroxylation was not detected in the liver microsomes from PenCB-treated rats. Immunochemical quantitation showed that in the microsomes from PenCB-treated rats, P-451 II, P-452,P-448 L and P-448 H accounted for 4.1,3.6,31.6 and 62.8%, respectively, of the total cytochrome P-450 (2.69 nmol/mg protein). On the other hand, the microsomal cytochrome P-450 in untreated rat livers (0.83 nmol/mg protein) consisted of 62.7% as P-451 II, less than 1% as P-452 and the remainder as P-451 I and other unknown forms. The results indicate that the unique change of the testosterone metabolism caused by PenCB-treatment might be due to both the considerable increase of P-452 as shown by 7α-hydroxylase and the marked decreases of other constitutive forms such as P-451 II and unknown form (s) involved in the 2α-, 6β- and 16α-hydroxy1ations.
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UNIQUE INDUCTION OF CYTOCHROME P-450 ISOZYMES IN RAT LIVER MICROSOMES BY TREATMENT WITH 3,4,5,3', 4'-PENTACHLOROBIPHENYL AND ITS EFFECT ON TESTOSTERONE METABOLISM

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