Comparative alterations in extrahepatic drug metabolism by factors known to affect hepatic activity

Abstract

Various factors known to alter hepatic drug metabolism were examined for their effects on drug metabolism in certain extrahepatic organs, viz. lung and kidney. The prominent sex-related differences in drug metabolism in rat liver were not seen in either lung or kidney. Pretreatment of rats with phenobarbital produced the expected large increases in hepatic NADPH cytochrome c reductase, cytochrome P-450. aminopyrine demethylase and biphenyl hydroxylase activities without concomitant changes in any of these parameters in lung, and only scattered and smaller changes in kidney. 3-Methylcholanthrene (3-MC) pretreatment significantly increased cytochrome P-450 levels in all three organs. Pretreatment of rats with carbon tetrachloride (CCl 4) produced consistent inhibition of mixedfunction oxidation in hepatic microsomes. but the extrahepatic effects were less predictable and were both organ- and enzyme-specific. An increase in renal UDP-glucuronyltransferase activity was observed after CCl 4 treatment that paralleled a similar but larger increase observed in liver. Extrahepatic NADPH cytochrome c reductase and N-methyl- p-chloroaniline demethylase values were unaffected by CCl 4. Lung and kidney responded in a like manner to liver to the additions in vitro of β-diethylaminoethyl diphenylpropylacetate (SKF-525A). Losses in enzyme activities in lung and kidney microsomes roughly paralleled those of liver when stored as pellets for up to 14 days at −70°. Two or 4 days of starvation produced substrate-specific changes in enzyme-specific activity in liver and kidney, with lung appearing resistant to the effect. When enzyme activity was expressed on a whole organ basis, however, lung cytochrome P-450 values decreased significantly and parameters from liver and kidney increased or decreased in a substrate-specific manner. It is concluded that some physiological and pharmacological factors that influence hepatic drug metabolism produce similar effects in lung and kidney, while other factors produce organ-specific effects.