The inhibition of CYP enzymes in mouse and human liver by pilocarpine

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Abstract
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 μm for COH and testosterone 15a-hydroxylase (T15αOH) activities, 4 μm for PROD, ≅ 100 μm for DMNA and testosterone 60-hydroxylase (T6βOH) activities and > 1 mm for EROD activity. 3 In human liver microsomes, the IC50 value for COH was 6 μm and for DMNA 10 μm; T15αOH and PROD activities were not detectable but T6βOH and testosterone 16β/2β-hydroxylase activities were moderately inhibited (IC50 70 μm). 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.