Alterations in Xenobiotic-Metabolizing Enzyme Activities across Menstrual Cycle in Healthy Volunteers

The purpose of the study was to determine whether the in vivo activities of drug-metabolizing enzymes CYP1A2 and CYP2A6, xanthine oxidase (XO), and N-acetyltransferase-2 (NAT2) vary across the menstrual cycle. Forty-two healthy women were studied at early follicular phase (EFP: 2nd to 4th days), late follicular phase (LFP: 10th to 12th days), and luteal phase (LP: 19th to 25th days) of a single menstrual cycle, and blood and urine samples were collected at each phase. Spot urine samples obtained 6 hours following 200-mg caffeine administration were used to determine caffeine metabolite ratios (CMRs); blood samples were used to determine CYP1A2*1F (rs762551) and CYP1A2*1C (rs2069514) polymorphisms and the hormonal profile (estradiol, progesterone, and luteinizing and follicle-stimulating hormones) at EFP, LFP, and LP. CMR and hormone variations were analyzed at three levels (EFP, LFP, LP) using one-way repeated-measures analysis of variance. CYP1A2 activity was lower and that of CYP2A6 and NAT2 were higher at LFP compared with EFP and LP. Enzyme alterations were significant in volunteers (n = 21) whose hormonal profiles at EFP, LFP, and LP corresponded to expected levels, but not in volunteers (n = 15) with presumed early or late sampling around LFP. No significant difference was detected in any enzyme activity in presumed anovulatory volunteers (n = 6). The reduction of CYP1A2 activity at LFP was not associated with smoking or CYP1A2*1F polymorphism. XO and NAT2 (fast acetylators) activities remained unaltered. It is suggested that drug-metabolizing enzyme activities are altered across the menstrual cycle. Selection of appropriate sampling periods verified by hormonal assessment and identification of anovulatory cycles are decisive factors in disclosing altered enzyme activity across the menstrual cycle.