Effect of suicide substrate on the metabolism of steroids and xenobiotics and on cytochrome P-450 apoproteins.

Abstract

Xenobiotic administration can significantly alter forms of hepatic microsomal cytochrome P-450. Individual forms of cytochrome P-450 are known to be increased by agents, such as phenobarbital, 3-methylcholanthrene, β-naphthoflavone and pregnenolone-16α-carbonitrile1–3. Certain chemicals decrease the levels of these isoenzymes by modulating the heme biosynthetic pathway and, thereby, affect the availability of heme and the amount of hepatic cytochrome P-450, e.g. cobaltous chloride4,5. Some agents can act as suicide substrates (i.e., mechanism-based inhibitors) for one or more cytochrome P-450 forms and, thereby, promote catabolic destruction of these cytochrome P-450 species6,7. Derivatives of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) interact rapidly with cytochrome P-450, promote the rapid destruction of hepatic microsomal cytochrome P-450 and lead to the generation in vivo of N-alkyl protoporphyrins which, in turn, inhibit the activity of mitochondrial ferrochelatase, the enzyme catalyzing the last step in heme biosynthesis8–11. The result is a decreased total hepatic microsomal cytochrome P-450 level and a marked hepatic porphyria12,13.