Metabolism of 6,7-dimethoxy 4-(4′-chlorobenzyl)isoquinoline. II. Role of liver catechol O-methyltransferase and glutathione

Abstract

1. On i.v. administration to rats of ¹⁴C-6,7-dimethoxy 4-(4′-chlorobenzyl)isoquinoline (PV2) 23% dose of ¹⁴C was excreted in urine and 72% in faeces. The pattern of metabolites showed ten ¹⁴C-PV2 derivatives and unchanged PV2. Seven metabolites have been characterized by comparison with authentic compounds e.g. the ketone of PV2, the N-oxide PV2, the demethylated metabolites 6-hydroxy-PV2, 7-hydroxy-PV2 and 6,7-dihydroxy PV2, the benzyl ring-hydroxylated metabolites, 3′-hydroxy-PV2 and 6,7,3′-trihydroxy-PV2. Unchanged PV2 and its metabolites are excreted both free and conjugated.

2. Enzymic O-methylation of 6,7-dihydroxy-PV2 by liver catechol-O-methyl transferase (COMT) in vitro produced 6-hydroxy, 7-methoxy-PV2. After blockade of COMT by pyrogallol in vivo, the excretion of 6,7-dihydroxy-PV2 was increased and the excretion of 6-hydroxy, 7-methoxy-PV2 decreased.

3. Hydroxylation of the benzyl ring of PV2 and its metabolites indicates the formation of an intermediate epoxide followed by glutathione conjugation. After glutathione depletion in vivo by diethyl maleate (DEM) liver covalent binding of ¹⁴C-PV2 metabolites was increased and biliary excretion of benzyl ring-hydroxylated PV2 metabolites decreased. Replacement of glutathione depletion by a cysteine derivative restored liver covalent binding and the excretion of PV2 metabolites to levels similar to those observed in control rats, indicating that glutathione conjugation may be an important metabolic pathway for the detoxication of PV2 and its metabolites in vivo.