Additional metabolic correlates of 1-alpha-acetylmethadol (LAAM)-induced cellular tolerance and physical dependence: the role of the hepatic microsomal electron transport system

Abstract

The microsomal cytochromes P-450 and b5 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-alpha-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 b5 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 b5 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.