Alteration of hepatic microsomal enzymes by griseofulvin treatment of mice.

Feeding mice a diet containing 2.5% griseofulvin (GF) for 12 days caused an increase in liver weight to 9 per cent of the body weight with a proportional decrease in microsomal protein/g of liver wet weight. With respect to microsomal protein, the cytochrome P-450 content was 50 per cent and cytochrome b₅ was 200 per cent of that in control mouse liver microsomes. The amount of increase in cytochrome b₅ was approximately the same as the amount of decrease in cytochrome P-450. and there was no change in the total microsomal heme content. The microsomal content of NADH-cytochrome b₅ reductase, as measured by ferricyanide reduction, was unchanged, but in agreement with the elevated cytochrome b₅ content, NADH-cytochrome c reductase activity was doubled. While the cytochrome P-450 level was low in microsomes after GF feeding, the NADPH-cytochrome c reductase was significantly elevated. Since this enzyme is generally considered to be rate limiting for many mixed function oxidase reactions, its increase may explain the normal to slightly elevated rates of metabolism in vitro of several type I and type II substrates. Although cytochrome b₅, has been suggested as being rate limiting for input of a second electron to cytochrome P-450 linked mixed function oxidations, elevation of cytochrome b₅ in the microsomes did not change the extent of NADH-synergism of NADPH-supported aminopyrine demethylation. NADH-supported Δ,10-fatty acid desaturase activity, which requires cytochrome b₅, was elevated several-fold after GF feeding. In contrast, NADPH-supported lipid peroxidation showed a slower onset after GF treatment; the NADH-supported reaction, however, was slightly elevated.