Effects of inducers and/or inhibitors on metabolism of lysergic acid diethylamide in rat liver microsomes

LSD metabolism in rat liver microsomes involves at least three separate enzyme systems. In untreated rats, the inhibitor SKF 525-A most potently blocked hydroxylation at the 13-position, moderately blocked N-demethylation at the 6-position, and least affected side-chain metabolism at the 8-position. A carbon monoxide/oxygen atmosphere (80% CO, 20% O2) caused maximum inhibition of N-demethylation, moderate inhibition of 13-hydroxylation, and minimum inhibition of side-chain metabolism. In microsomes from rats pretreated with 3-methylcholanthrene, 13-hydroxylation was not inhibited by CO but still required NADPH and oxygen, suggesting catalysis by an unusual cytochrome P-448 enzyme system.

Study at a glance

Abstract

1. When lysergic acid diethylamide (LSD) was incubated with liver microsomes obtained from untreated rats, SKF 525-A inhibited most potently the hydroxylation at the 13-position, moderately inhibited N-demethylation at the 6-position, and least affected the metabolism of the side-chain at the 8 position. Furthermore, an atmosphere of 80% CO and 20% O2 (v/v) caused max. inhibition in N-demethylation, moderate inhibition in 13-hydroxylation, and the minimum in metabolism of the side-chain at the 8-position. These data suggested that the metabolism of LSD is catalysed by three separate enzyme systems. 2. The formation of 13-hydroxy-lysergic acid diethylamide (13-hydroxy-LSD) in liver microsomes obtained from 3-methylcholanthrene-treated rats was not inhibited by CO, although the hydroxylation required NADPH and oxygen. 3. The results of experiments using various inhibitors suggest that the 13-hydroxylation in liver microsomes from 3-methylcholanthrene-treated rats is catalysed by an enzyme system involving an unusual type of cytochrome P-448.