Molecular Pharmacology, Vol 18, 304-312, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Phenobarbital, Pregnenolone-16-Carbonitrile, and 3-Methyicholanthrene Pretreatments on the Distribution of NADPH-Cytochrome c(P-450) Reductase within the Liver Lobule

¹ The Toxicology Center, Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa 52242

The effects of phenobarbital, pregnenolone-16-carbonitrile, and 3-methylcholanthrene pretreatments on the distribution of NADPH-cytochrome c (P-450) reductase (NADPH: ferricytochrome oxidoreductase, EC 1.6.2.4) within the livers of male rats were investigated employing sheep antiserum produced against rat hepatic microsomal NADPH-cytochrome c reductase in indirect fluorescent antibody and unlabeled antibody peroxidase-antiperoxidase immunohistochemical staining techniques. In the livers of untreated and vehicle-pretreated rats, the extent of binding of the antireductase to hepatocytes was found to be similar within the centrilobular and midzonal regions of the lobule but significantly lower within the periportal regions of the lobule. Pretreatment of rats for 4 days with 3-methylcholanthrene did not result in alterations in either the pattern or the intensity of immunohistochemical staining for the reductase within the liver lobule. In the livers of rats which had been pretreated for 4 days with phenobarbital, microfluorometric analyses revealed a twofold increase in the extent of antireductase binding to hepatocytes within all regions of the lobule. In contrast to the effects of phenobarbital, pregnenolone-16-carbonitrile markedly altered the pattern as well as the intensity of immunohistochemical staining for NADPH-cytochrome c (P-450) reductase within the liver lobule. After 4 days of pregnenolone-16-carbonitrile pretreatment, there was a threefold increase in the extent of antireductase binding to hepatocytes within the periportal regions of the lobule, while the extent of antireductase binding to centrilobular and midzonal hepatocytes was increased by only 73 and 45%, respectively. Thus, in the livers of pregnenolone-16-carbonitrile-pretreated rats, the antireductase bound to a similar extent to periportal and midzonal hepatocytes and to a significantly greater extent to centrilobular hepatocytes. These results demonstrate that, although both phenobarbital and pregnenolone-16-carbonitrile induce NADPH-cytochrome c (P-450) reductase in hepatocytes throughout the liver lobule, phenobarbital appears to produce a uniform induction of the reductase within the lobule, while pregnenolone-16-carbonitrile induces the reductase by significantly different extents within the three lobular regions.

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