alexa Changes in glutathione and cellular energy as potential mechanisms of papaverine-induced hepatotoxicity in vitro.
Pharmaceutical Sciences

Pharmaceutical Sciences

Pharmaceutica Analytica Acta

Author(s): Davila JC, Davis PJ, Acosta D

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Abstract The purpose of this study was to elucidate the mechanism of hepatotoxicity of papaverine hydrochloride (papaver) in vitro. To evaluate the role of metabolism in the toxicity of papaver, cells were pretreated with SKF-525A or benzyl imidazole (cytochrome P450 system inhibitors) for 24 hr at 1 x 10(-5) or 1 x 10(-4) M, respectively, or with phenobarbital sodium (cytochrome P450 system inducer) for 3 days at 2 x 10(-3) M. Cells then were exposed to concentrations of papaver ranging from 1 x 10(-5) to 1 x 10(-3) M for 4 to 24 hr. Cytotoxicity was evaluated by enzyme leakage (lactate dehydrogenase) and by energy status of the cells (ATP/ADP). The role of biological reactive intermediates in the toxicity of papaver was investigated by measuring changes in cellular reduced glutathione levels (GSH), by inhibiting GSH synthesis, and by determining the production of lipid peroxidation (LPX). Papaverine produced concentration- and time-dependent increases in enzyme leakage, with significant effects occurring by the 8-hr exposure period. Pretreatment with SKF-525A or benzyl imidazole increased enzyme leakage induced by papaver especially at a later time frame (24 hr), but pretreatment with phenobarbital delayed the onset of cytotoxicity from 8 to 12 hr. Decreases in GSH levels paralleled the time course of enzyme leakage. However, the administration of buthionine sulfoximine to cell cultures dramatically decreased the time by which papaver induced cellular injury (2 hr vs 8 hr). Changes in cellular energy status (ATP/ADP) were also detected earlier than enzyme leakage (4 hr vs 8 hr). In contrast, no significant production of lipid peroxidation was noted in papaver-treated cultures. We suggest that the mechanism of papaver-induced hepatotoxicity may be related to alterations in glutathione balance of the cells and to disruption of energy homeostasis.
This article was published in Toxicol Appl Pharmacol and referenced in Pharmaceutica Analytica Acta

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