Introduction There is an unpredictable relationship between thiopurine methyl transferase (TPMT) and hypermethylation. It is likely that cytochrome P450 (CYP450) enzymes play a role in the demethylation of methylated mercaptopurine (MMP), altering the MMP:Thioguanine nucleotide (TGN) ratio(Table 1). Smoking has been shown to induce CYP450 enzymes. One study on smoking and olanzapine demonstrated a 6 fold increase in CYP450 activity through smoking.1 This might suggest that smoking could upregulate the demethylation process, reducing MMP.
Methods Patients on thiopurines had their smoking status recorded as they attended the inflammatory bowel disease (IBD) clinic. Retrospective data on demographics was collected (Table 1). Only measurable TGNs after 6 weeks of therapy were used for analysis. Metabolites measured whilst on allopurinol were excluded. Average TGNs over the treatment period, MMP and MMP:TGN ratios were compared between smokers and non-smokers. Hypermethylators were defined as any patient with an MMP:TGN ratio of ≥11 during their treatment
Results 230 patients were analysed(117 males).
Table 1 shows comparison in demographics between smokers and non-smokers
Mean MMP for smokers was 1683(SD 2565, median 840) versus 2041 in non-smokers(SD 2401, median 1340)(P = 0.713). Mean MeMP:TGN ratio for smokers was 6.15 (SD 9.06, median 2.22) versus 7.81 in non-smokers (SD 8.01, median 4.70)(P = 0.593).
Conclusion There were more hypermethylators in the non-smoking cohort than in the smoking cohort (42.7% versus 28.3%(P < 0.05)), however the difference between average MMP and MMP:TGN ratios were not significant although the median differences are compelling. There were significant differences between quantity smoked and the MMP:TGN ratio. Paradoxically, the reduction in methylation if smoking <5 cigarettes/day was reversed when smoking ≥15 cigarettes/day. This may suggest an alternative pathway affected by smoking. Smoking status and quantity should be taken into account when monitoring metabolites. Additionally, polymorphisms for CYP450 (CYP1A2*F and CYP1A2*1 C), known to affect drug metabolism between individuals, may be responsible for variation and require further research.
Reference 1 Carrillo JA, Herráiz AG, Ramos SI, Gervasini G, Vizcaíno S, Benítez J. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol. 2003 Apr;23(2):119–27.
Disclosure of Interest None Declared