Rat liver microsomes metabolize LSD into several products. Two previously reported metabolites, lysergic acid ethylamide and nor-LSD, were found alongside two newly identified ones: lysergic acid ethylvinylamide, formed by dehydrogenation of the side chain, and 13-hydroxy-LSD, a phenol. Pretreatment of rats with phenobarbitone sodium induced formation of lysergic acid ethylamide, lysergic acid ethylvinylamide, and nor-LSD, while 3-methylcholanthrene induced lysergic acid ethylamide, lysergic acid ethylvinylamide, and 13-hydroxy-LSD. Nor-LSD formation was induced only by phenobarbitone, and 13-hydroxy-LSD only by methylcholanthrene.
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.