EFFECT OF THE SUICIDE SUBSTRATE 3,5-DIETHOXYCARBONYL-2,6-DIMETHYL-4-ETHYL-1,4-DIHYDROPYRIDINE ON THE METABOLISM OF XENOBIOTICS AND ON CYTOCHROME-P-450 APOPROTEINS

  • 1 January 1986
    • journal article
    • research article
    • Vol. 29  (1) , 81-87
Abstract
Treatment of rats with the cytochrome P-450 suicide substrate, 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (DDEP), produced a 95% inhibition of the in vivo demethylation of either aminopyrine or morphine within 2 hr. One-carbon metabolism of formaldehyde or formate to carbon dioxide was not altered. DDEP also produced a time-dependent decrease in total hepatic microsomal cytochrome P-450 but had no effect on either NADPH-cytochrome c reductase or p-nitrophenol glucuronyltransferase activities up to 24 hr after administration. A rapid decrease in rat liver microsomal aniline hydroxylation and ethoxyresorufin deethylation was observed in vitro following DDEP administration. Although in vitro testosterone metabolism to 16.alpha.-, 16.beta.-, and 2.alpha.-hydroxy metabolites was depressed profoundly by DDEP in microsmes from untreated and 3-methylcholanthrene-treated animals, 7.alpha.-hydroxylation of testosterone was much less affected. Immunochemical quantification of various microsomal cytochrome P-450 protein moieties showed that cytochromes P-450.beta.NF-B, P-450UT-A, P-450PCN-E, and P-450PB-C were decreased in hepatic microsomes from DDEP-treated rats. However, the protein moiety of cytochrome P-450UT-H was not diminished and the immunoreactive protein for cytochromes P-450UT-F, P-450PB-B, and P-450ISF-G was only slightly decreased. These results show that DDEP treatment leads to marked decreases in holoprotein and apoproteins of many but not all hepatic microsomal cytochrome P-450 isozymes.

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