3,4,5-Trimethoxyphenylacetaldehyde, an Intermediate Metabolite of Mescaline, Is a Substrate for Microsomal Aldehyde Oxygenase in the Mouse Liver.
Biological and Pharmaceutical Bulletin – January 01, 1995
Source: OpenAlex
Summary
3,4,5-Trimethoxyphenylacetaldehyde, a metabolite of mescaline, undergoes oxidation to form 3,4,5-trimethoxyphenylacetic acid in mouse hepatic microsomes at a rate of 0.96 nmol/min/nmol P450. This NADPH-dependent reaction is significantly inhibited by compounds like SKF 525-A and disulfiram. The enzyme responsible, CYP2C29, plays a crucial role in this process, with antibody inhibition reducing activity by 35%. Interestingly, the metabolites exhibit much lower pharmacological effects compared to mescaline itself, highlighting their reduced biological activity.
Abstract
3,4,5-Trimethoxyphenylacetaldehyde, an intermediate metabolite of mescaline, was oxidized to 3,4,5-trimethoxyphenylacetic acid by mouse hepatic microsomes. The reaction was NADPH-dependent, and inhibited by SKF 525-A, metyrapone and disulfiram. A P450 isozyme in mouse hepatic microsomes, P450 MUT-2 (CYP2C29), catalyzed the reaction (0.96 nmol/min/nmol P450) in which NADPH and NADPH-cytochrome c reductase were essential for the catalytic activity. The reaction was confirmed to be an oxygenation since molecular oxygen was incorporated into the carboxylic acid metabolite formed under oxygen-18 gas by GC-MS analysis. By addition of antibody against CYP2C29 to the microsomes (3.2 mg/mg microsomal protein) the MALDO activity was inhibited by 35% of the control value with preimmune serum, suggesting that CYP2C29 or an immunologically-related isozyme(s) plays a major role in the NADPH-dependent oxidation of 3,4,5-trimethoxyphenylacetaldehyde to 3,4,5-trimethoxyphenylacetic acid by mouse hepatic microsomes. Pharmacological experiments on mescaline and its deaminated metabolites using mice indicated that the metabolites were much less active or were inactive in cataleptogenic effect and pentobarbital-induced sleep prolongation as compared with the parent compound.