RT Journal Article
SR Electronic
T1 Metabolism of the beta-carbolines, harmine and harmol, by liver microsomes from phenobarbitone- or 3-methylcholanthrene-treated mice. Identification and quantitation of two novel harmine metabolites.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 74
OP 81
VO 15
IS 1
A1 D J Tweedie
A1 M D Burke
YR 1987
UL http://dmd.aspetjournals.org/content/15/1/74.abstract
AB This study extends an investigation of the metabolism of the beta-carbolines, harmine and harmol, by untreated, phenobarbitone-induced, or 3-methylcholanthrene (MC)-induced mouse liver microsomes to identify two MC-inducible metabolites of harmine and to quantitate their rates of formation using 3H-labeled substrate. An HPLC system was devised to separate harmine and its metabolites. The major metabolite with MC-induced microsomes was identified by mass spectroscopy and by NMR to be 6-hydroxy-7-methoxyharman and was produced at an initial reaction rate of 11 nmol/min/mg of microsomal protein (27-fold induction). The other novel metabolite, 3- or 4-hydroxy-7-methoxyharman (the position of the hydroxyl group could not be definitively assigned by NMR) was produced at an initial reaction rate of 3.8 nmol/min/mg of microsomal protein (32-fold induction) which was similar to the rate of formation of the other metabolite, harmol, determined previously. All three metabolites were further metabolized to unidentified metabolites. Protein binding of [3H]harmine and [3H]harmol was measured and shown to be metabolism dependent. It was also noted that the alkali conditions used for optimal extraction stimulated the protein binding.