Further studies on the in vivo effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on the liver microsomal drug oxidation system in rats

Abstract

The effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on microsomal electron transport systems in relation to drug oxidation was studied in rat liver. A single oral dose (250 mg/kg) of NKK-105 increased the ratio of liver to body weight, the microsomal protein content, the cytochrome b 5 content, and the NADPH cytochrome c reductase activity at 24–48 hr after drug administration. The cytochrome P-450 content was decreased at 2–6 hr and slightly increased at 24–48 hr after drug administration. Upon daily administration of NKK-105 at a dose of 250 mg · kg −1 · day −1 for 21 days, cytochrome b 5 content and NADPH cytochrome c reductase activity were increased, but cytochrome P-450 content and NADH cytochrome b 5 reductase activity remained unchanged. Despite the increase of NADPH cytochrome c reductase activity, NADPH-dependent lipid peroxidation tended to decrease rather than increase. NADPH stearoyl-CoA desaturase activity increased prior to the increase of cytochrome b 5. Benzphetamine N-demethylase and p-nitroanisole O-demethylase activities were enhanced, accompanied by an increase of cytochrome b 5. Aniline hydroxylase activity was decreased by NKK-105 administration. These results indicate that the induction pattern of liver microsomal electron transport systems by NKK-105 is characteristic.