Demonstration in multiple species of inducible hepatic cytochromes P- 450 and their mRNAs related to the glucocorticoid-inducible cytochrome P-450 of the rat

SA Wrighton, EG Schuetz, PB Watkins, P Maurel, J Barwick, BS Bailey, HT Hartle, B Young and P Guzelian

We have recently demonstrated that P-450p, a form of rat liver cytochrome P-450 inducible by steroids such as dexamethasone and pregnenolone-16 alpha-carbonitrile, by the macrolide antibiotic triacetyloleandomycin, and by phenobarbital, is immunochemically related to and shares 73% NH2-terminal amino acid sequence homology with rabbit cytochrome LM3c. Extending this interspecies comparison we now report that liver microsomes prepared from the rabbit, hamster, gerbil, and mouse contain inducible cytochromes P-450 that resemble P- 450p in: (a) converting triacetyloleandomycin to a metabolite that forms a distinct spectral complex with cytochrome P-450 heme, (b) catalyzing the demethylation of erythromycin, and (c) reacting on immunoblots with antibodies directed against P-450p or LM3c. These three characteristics changed in parallel within treatment groups of a given species receiving different inducers of cytochrome P-450. However, there were striking qualitative and quantitative interspecies differences in the responses to inducers. For example, rifampicin was the most efficacious inducer of LM3c in the rabbit and yet was not at all an inducer of P-450p in the rat whereas pregnenolone-16 alpha- carbonitrile, an inducer in the rat, failed to induce LM3c in the rabbit. Immunoblot analysis of these microsomes revealed in each species except the rabbit a single immunochemically related protein. A second immunoreactive protein was present in microsomes from male and female and rifampicin- and dexamethasone-treated female rabbits. Two cloned cDNAs, which hybridized to a species of liver mRNA directing the synthesis of P-450p in a cell-free translation system, were used to probe Northern blots of liver RNAs. These revealed a single band of hybridizable mRNA in each species (except RNA from the rabbit which gave no signal even under conditions of reduced stringency) that was induced in qualitative proportions to that of the accumulated immunoreactive protein. We conclude that P-450p appears to be conserved in evolution and is represented in each of the species tested by one or more immunochemically related proteins which exhibit similar catalytic activities to those of P-450p.

Volume 28, Issue 3, pp. 312-321, 09/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics

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