Cytochrome P450 and its interactions with the heme biosynthetic pathway.

An important factor in disruption of hepatic heme biosynthesis by porphyrinogenic drugs appears to be interaction with one or several cytochrome P450 isozymes. Clarification of the nature of the interaction between porphyrinogenic drugs and cytochrome P450 isozymes, as well as identification of the isozymes involved, will be helpful in extrapolating the results of animal experimentation to humans. Administration of griseofulvin to mice results in accumulation in the liver of two N-alkylated protoporphyrins (PPs). The major N-alkyl PP, N-griseofulvin PP, which is devoid of ferrochelatase-inhibitory activity, was shown to be the precursor of N-methyl PP, which is a potent ferrochelatase inhibitor. N-Griseofulvin PP was present predominantly as the Nc regioisomer rather than the anticipated NA regioisomer. Progesterone (PG) 6 beta-hydroxylase and androstenedione (AD) 6 beta-hydroxylase, diagnostic markers for cytochrome P450 3A1/2 activity in rat liver, were identified in chick embryo liver. The in ovo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC) and 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) caused inactivation of chick embryo hepatic PG and AD 6 beta-hydroxylases. Ascorbate was shown to inhibit uroporphyrin accumulation in cultures of chick embryos treated with porphyrinogenic drugs and in the livers of an ascorbate-requiring rat strain treated with a porphyrinogenic combination of chemicals. Ascorbate appears to act by inhibiting oxidation of uroporphyrinogen to uroporphyrin. Avian hepatocytes were cultured in 48-well plates and directly assayed within the wells for the activity of 7-ethoxyresorufin O-deethylation (EROD), and for porphyrin and protein concentration by a fluorescence plate reader. Uroporphyrin was the main porphyrin to accumulate in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in chick embryos, pheasants, ducks, and herring gulls; heptacarboxylated porphyrin predominated in turkey hepatocytes. The EROD-inducing potential of complex mixtures of polyhalogenated aromatic hydrocarbons from herring gull eggs was assessed and compared with that of TCDD. A nuclear heme pool appears to regulate the transcription of the cytochrome P450 2B1/2B2 genes in rat liver, by modulating binding of a transcription factor(s) that appears to be involved in the transcriptional activation by phenobarbitone.