Aromatization of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline by rat liver microsomes

The in vitro aromatization of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (DCTQ) has been studied. Incubation of DCTQ with various rat liver subcellular fractions in the presence and absence of cofactors suggested that oxidative reactions catalyzed by microsomal enzymes were involved in this aromatization pathway. In addition to the aromatization product, 7,8-dichloroisoquinoline, three other metabolites were detected in the 9000g supernatant and microsomal incubations. By comparing the chromatographic and spectral data of the metabolites with those obtained for synthetic compounds, these three metabolites were identified as the hydroxylamine, nitrone, and the partially oxidized product (3,4-dihydro) of DCTQ. When added to microsomes, the hydroxylamine and the 3,4-dihydro derivatives were also metabolized to the 7,8-dichloroisoquinoline, and the conversions were NADPH and oxygen dependent. These findings, together with kinetic data, suggested that the aromatization of DCTQ catalyzed by rat liver microsomes was a stepwise oxidative reaction, with N-hydroxylation of DCTQ as the initial step.