An assessment of the potential of protopine to inhibit microsomal drug metabolising enzymes and prevent chemical-induced hepatotoxicity in rodents

The potential of protopine to inhibit microsomal drug metabolising enzymes (MDME) and prevent paracetamol- and CCl4-induced hepatotoxicity was studied in rats. Paracetamol at the dose of 640 mg kg(-1) produced hepatic damage in rats as manifested by the rise in serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) to 972 +/- 186 and 624 +/- 131 IU (mean +/- SEM; n = 10), respectively, compared to respective control values of 101 +/- 29 and 64 +/- 18 IU. Pretreatment of rats with protopine (11 mg kg(-1), orally twice daily for 2 days) lowered significantly the respective serum AST and ALT levels (P < 0.05) to 289 +/- 52 and 178 +/- 43 IU. The hepatotoxic dose of CCl4 (1.5 ml kg(-1); orally) raised serum AST and ALT levels to 543 +/- 189 and 387 +/- 69 IU (mean +/- SEM; n = 10), respectively, compared to respective control values of 98 +/- 28 and 56 +/- 17 IU. The same dose of protopine (11 mg kg(-1)) was able to prevent significantly (P < 0.05), the CCl4-induced rise in serum enzymes and the estimated values of AST and ALT were 168 +/- 36 and 93 +/- 28 IU, respectively. Protopine caused prolongation (P < 0.05) in pentobarbital (55 mg kg(-1))-induced sleep as well as potentiated strychnine-induced toxicity in rats, suggestive of an inhibitory effect on MDME. These results indicate that protopine exhibits anti-hepatotoxic action which may be mediated through inhibition of MDME. (C) 1998 The Italian Pharmacological Society.