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

1 Pilocarpine is a cholinomimetic natural alkaloid. Its interactions w ith testosterone hydroxylations, coumarin 7-hydroxylase (COH), dimethy lnitrosamine N-demethylase (DMNA), pentoxyresorufin O-dealkylase (PROD ) and 7-ethoxyresorufin O-deethylase (EROD), which are indicative of t he activities of cytochrome P4502A5 (CYP2A5) or 6, 2E1, 2B, 1A, were e xamined in mouse and human liver microsomes. 2 In mouse liver microsom es 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, appr oximate to 100 mu M for DMNA and testosterone 6 beta-hydroxylase (T6 b eta OH) activities and > mM for EROD activity. 3 In human liver micros omes, the IC50 value for COH was 6 mu M and for DMNA 10 mu M; T15 alph a OH and PROD activities were not detectable but T6 beta OH and testos terone 16 beta/2 beta-hydroxylase activities were moderately inhibited (IC50 70 mu M). 4 These results suggest that pilocarpine has (i) a hi gh affinity towards phenobarbitone-inducible CYP2A4/5 and CYP2B activi ties in mouse liver, (ii) a high affinity towards CYP2A6 in human live r microsomes and (iii) a moderate affinity towards CYP3A enzyme(s) in both microsomal preparations. 5 The low IC50 concentrations in vitro i ndicate potential metabolic interactions between pilocarpine and sever al P450 enzymes.