The Possible Role of Glutathione on the Hepatotoxic Effect of Papaverine Hydrochloride in Vitro

Abstract

Papaverine hydrochloride (papaver) is an isoquinoline alkaloid widely used as a smooth muscle relaxant agent. It is metabolized mainly in the liver by the P-450 system (O-demethylation) to yield several phenolic metabolites (4’-,6-, 7-, 3’-, and 4’,6- demethylated phenols) (Belpaire et al., 1975). Papaver induces hepatotoxicity by an idiosyncratic immune effect (Kiaer et al., 1974) or a direct metabolite-related hepatocellular toxic effect (Acosta et al., 1980; Davila et al., 1989). At the present time, however, there is no direct evidence which suggests that toxic metabolites derived from papaver are responsible for liver cell injury. We had demonstrated previously that a time lag of 6 hr was necessary before papaver injured cultured hepatocytes and that the papaver-phenolic metabolites were considerably less toxic than the parent compound. They were ranked in toxicity as follows: papaver>60H>4’0H>3’OH (Acosta et al., 1980; Davila et al., 1989). According to these results, it seems that the metabolite(s) is (are) not the major cause of liver injury. It is interesting to note, however, that certain principal metabolites of papaver are nearly as toxic as the parent compound, while others clearly represent detoxification pathways; therefore, we can not rule out the possibility that papaver-derived intermediate metabolite(s) is (are) involved in the toxic insult. Some mechanistic alternatives are suggested: 1) papaver itself may be directly responsible for cellular toxicity or be metabolized to toxic products by a pathway not involving O-dealkylation; 2) phenol formation (e.g. at 4’-position) may require an additional O-dealkylation or aromatic hydroxylation to yield a catechol which may undergo oxidation to a reactive ortho-quinone; 3) quinone-methides may be formed following O-dealkylation (Figure 1); and 4) the time lag of 6 hr may represent the time required for bioconversion and accumulation of sufficient quantities of toxic metabolites and/or saturate and deplete intracellular glutathione stores.