Additional metabolic correlates of l-α-acetylmethadol (LAAM)-induced cellular tolerance and physical dependence: The role of the hepatic microsomal electron transport system

Abstract The microsomal cytochromes P-450 and b 5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25–30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l - α -acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b 5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b 5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.