THE INHIBITION OF CYP ENZYMES IN MOUSE AND HUMAN LIVER BY PILOCARPINE

1 Pilocarpine is a cholinomimetic natural alkaloid. Its interactions with testosterone hydroxylations, coumarin 7-hydroxylase (COH), dimethylnitrosamine N-demethylase (DMNA), pentoxyresorufin O-dealkylase (PROD) and 7-ethoxyresorufin O-deethylase (EROD), which are indicative of the activities of cytochrome P4502A5 (CYP2A5) or 6, 2E1, 2B, 1A, were examined in mouse and human liver microsomes. 2 In mouse liver microsomes the IC50 values of pilocarpine were 6 mu M for COH and testosterone 15 alpha-hydroxylase (T15 alpha OH) activities, 4 mu M for PROD, approximate to 100 mu M for DMNA and testosterone 6 beta-hydroxylase (T6 beta OH) activities and > mM for EROD activity. 3 In human liver microsomes, the IC50 value for COH was 6 mu M and for DMNA 10 mu M; T15 alpha OH and PROD activities were not detectable but T6 beta OH and testosterone 16 beta/2 beta-hydroxylase activities were moderately inhibited (IC50 70 mu M). 4 These results suggest that pilocarpine has (i) a high affinity towards phenobarbitone-inducible CYP2A4/5 and CYP2B activities in mouse liver, (ii) a high affinity towards CYP2A6 in human liver microsomes and (iii) a moderate affinity towards CYP3A enzyme(s) in both microsomal preparations. 5 The low IC50 concentrations in vitro indicate potential metabolic interactions between pilocarpine and several P450 enzymes.