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P349 The effects of smoking on thiopurine metabolism

B. Warner*1, E. Johnston1, S. Fong1, P. Blaker1, M. Arenas-Hernandez2, A. Marinaki2, J. Sanderson1

1Guy’s and St Thomas’ NHS Foundation Trust, Gastroenterology, London, United Kingdom, 2Guy’s and St Thomas’ NHS Foundation Trust, Purine Laboratory, Viapath, London, United Kingdom

Background

There is an unpredictable relationship between TPMT and hypermethylation. It is likely that cytochrome P450 (CYP450) enzymes play a role in the demethylation of methylated mercaptopurine (MMP), altering the MMP:TGN ratio. Smoking has been shown to induce CYP450 enzymes. One study on smoking and olanzapine demonstrated a 6-fold increase in CYP450 activity through smoking. This suggests that smoking could upregulate the demethylation process, reducing MMP.

Methods

Patients on thiopurines had their smoking status recorded as they attended clinic. Retrospective data on demographics was collected. 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.

Table 1. Comparison in demographics between smokers and non-smokers

Smokers n = 106Non-smokers n = 124
Male: female51%:49%47%:53%
Age3733
Ethnicity: white, black, 
or other81%:19%:0%80%:9%:11%
Crohn’s: ulcerative colitis82%:18%72%:27%
Previous surgery45%27%
Mean TPMT38.4 (median 35)34.1 (median 35)
Hepatotoxicity15.1%13.7%
Hypermethylation28.3%42.7%

Mean MMP for smokers was 1683(SD 2 565, median 840) vs 2 041 in non-smokers (SD 2 401, median 1 340, p = 0.713). Mean MeMP:TGN ratio for smokers was 6.15 (SD 9.06, median 2.22) vs 7.81 in non-smokers (SD 8.01, median 4.70, p = 0.593). This compared with 4.85 for smoking between 1 and 4 cigarettes (p < 0.05), 6.35 for those smoking between 5 and 14 (p = 0.691), and 9.23 for between 15 and 24 cigarettes/day (p < 0.05).

Figure 1. Box plot showing relationship between average MMP:TGN ratios in non-smokers vs smokers.

Figure 2. Box plot showing comparison between quantity/day and average MMP:TGN ratio.

Conclusion

There were more hypermethylators in the non-smoking cohort than in the smoking cohort (42.7% vs 28.3% [p < 0.05]); however, the difference between average MMP and MMP:TGN ratios were not significant although 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*1C), known to affect drug metabolism between individuals, may be responsible for variation and require further research.