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RESEARCH PRODUCT

INDUCTION OF CYTOCHROME P-448 BY 3-METHYLCHOLANTHRENE IN THE RAT DURING INHIBITION OF PROTEIN SYNTHESIS IN VIVO

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Administration of cycloheximide in vivo during induction of rats with 3-methylcholanthrene prevents the increase in total cytochrome P-450 content usually seen under the influence of the inducer. The population of cytochromes P-450 in the livers of these animals is, however, similar to that in the completely induced animals. Microsomal aryl hydrocarbon hydroxylase activity and biphenyl-2-hydroxylation are enhanced severalfold and biphenyl-4-hydroxylation is enhanced twofold. Monooxygenase activity shows the same pattern of preferential inhibition as in microsomes from animals which had received the inducer only. The affinity of the reduced cytochromes for the ligand metyrapone is considerably decreased both after treatment with 3-methylcholanthrene and with 3-methylcholanthrene plus cycloheximide. A distinct blue shift of the absorbance maxima of the reduced P-450-CO complex and of the reduced P-450-metyrapone complex occurs after concomitant treatment with the inducer and the inhibitor of protein synthesis. The pattern of cytochrome P-450 bands after SDS polyacrylamide gel electrophoresis of microsomes from animals treated with both drugs is similar to that of MC-stimulated microsomes but different from that of control microsomes. These data show that during inhibition of protein synthesis in vivo 3-methylcholanthrene induces the same pattern of cytochromes P-450 as under normal conditions of induction while the increase in total cytochrome P-450 content is almost completely prevented.