Molecular Pharmacology, Vol 11, 190-200, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Neonatal Imprinting and the Turnover of Microsomal Cytochrome P-450 in Rat Liver

¹ Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110

Administration of [3,5-³H]-aminolevulinic acid to immature and adult male and female rats led to the incorporation of radioactivity into liver microsomal cytochrome P-450. A biphasic decrease was observed in the radioactivity incorporated into the hemeprotein, and the half-lives were 7-8 and 42-46 hr in all cases, suggesting that at least two forms of cytochrome P-450 exist in rat liver microsomes. The ratio of the fast-phase component to the slow-phase component was 3.4-4.4:1 in the immature and adult female and the immature male rat. This ratio changed to 1.9:1 in the adult male, indicating an age and sex difference in the ratio of the two forms of the cytochrome. Castration of the male at 4 weeks of age did not prevent the change in ratio that occurred during the next 4 weeks. However, castration of male rats at birth prevented the age-dependent change in ratio that occurred after 4 weeks of age and resulted in a biphasic turnover of cytochrome P-450 that was indistinguishable from that of the adult female rat. These changes in cytochrome P-450 were correlated with changes in the activity of liver microsomal enzymes that hydroxylate testosterone at the 7, 16, and 6 positions. Different ratios of activities of the three hydroxylation reactions are characteristic of the immature and adult male and female rat. Castration of male rats at birth caused the development of a female pattern of testosterone hydroxylation, whereas castration at 4 weeks of age resulted in a pattern of hydroxylation that was intermediate between the adult male and female.

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ACKNOWLEDGMENT We thank Mrs. C. Chvasta for her assistance in the preparation of this manuscript.