Oxidative metabolism of the bioactive and naturally occurring β-carboline alkaloids, norharman and harman, by human cytochrome P450 enzymes

摘要

Norharman and harman are naturally occurring β-carboline alkaloids exhibiting a wide range of biological, psychopharmacological, and toxicological actions. They occur in foods and tobacco smoke and also appear endogenously in humans. In this research, metabolic and kinetic studies with cytochrome P450 enzymes and human liver microsomes showed that β-carbolines were efficiently oxidized to several ring-hydroxylated and N-oxidation products that were subsequently identified and quantified. 6-Hydroxy-β-carboline (6-hydroxynorharman and 6-hydroxyharman) was a major metabolite efficiently produced (high kcat and low Km) by P450 1A2 and 1A1 and to a minor extent by P450 2D6, 2C19 and 2E1. 3-Hydroxy-β-carboline (3-hydroxynorharman and 3-hydroxyharman), another major metabolite, was specifically produced by P450 1A2 and 1A1, whereas β-carboline-N(2)-oxide (harman-2-oxide and norharman-2-oxide) was produced by P450 2E1. The same pattern of metabolism was confirmed for human liver microsomes. Oxidative metabolism for harman was slightly higher than norharman, but norharman showed lower Km values. The oxidation of β-carbolines is a detoxication route performed mainly by P450 1A2 and 1A1, with the participation of P450 2D6, 2C19, and 2E1, as additional contributors. Then, individual variations in the levels and activity of these P450s may influence biotransformation of β-carboline alkaloids and their ultimate biological effects. β-Carbolines were previously reported as comutagens and/or inhibitors of mutagens activated by P450 1A enzymes such as heterocyclic amines and polycyclic hydrocarbons. Results in this work show that β-carbolines are good ligands and substrates for P450 1A2/1A1, contributing to the explanation of some of their toxicological effects. © 2008 American Chemical Society.