Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking

Background Cytochrome P4501A2 (CYP1A2) presents a high interindividual variability in its activity and also in its inducibility by smoking. Cytochrome P450 oxidoreductase (POR) is an electron transfer protein that catalyzes the activity of several cytochromes P450. We aimed to study the influence of POR genetic polymorphisms on CYP1A2 activity while smoking and after smoking cessation, as well as on CYP1A2 inducibility. Methods CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and in 113 of these smokers who were abstinent during a 4-week period. Participants were genotyped for POR rs17148944G > A, rs10239977C > T, rs3815455C > T, rs2286823G > A, rs2302429G > A, and rs1057868C > T (POR*28) polymorphisms. Results While smoking, none of the tested POR polymorphisms showed a significant influence on CYP1A2 activity. After smoking cessation, significantly higher CYP1A2 activity was found in POR rs2302429A carriers (P = 0.038) and in carriers of rs17148944G-rs10239977C-rs3815455T-rs2286823Grs2302429A-rs1057868T haplotype (P = 0.038), whereas carriers of POR rs2286823A (P = 0.031) and of the rs17148944G-rs10239977C-rs3815455C-rs2286823Ars2302429G-rs1057868C haplotype (P = 0.031) had decreased CYP1A2 activity. In the complete regression model, only POR rs2302429G > A showed a significant effect (P = 0.017). No influence of POR genotypes or haplotypes was observed on the inducibility of CYP1A2. Conclusion POR genetic polymorphisms influence CYP1A2 basal but not induced activity and do not seem to influence CYP1A2 inducibility. Future work is warranted to identify other clinical and genetic factors that may explain the variability in CYP1A2 activity and inducibility by smoking. Pharmacogenetics and Genomics 22: 143-151 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.