Objectives Major risk factors for hepatocellular carcinoma (HCC) are hepatitis viruses and exposure to aflatoxins, including aflatoxin B1 (AFB1). The mutagenic effect of AFB1 results from hepatic bioactivation to AFB1-exo-8,9-epoxide. This is in part catalysed by CYP3A5, an enzyme expressed polymorphically. We investigated the role of CYP3A5 polymorphisms in the formation of AFB1-exo-8,9-epoxide in The Gambia, a population exposed to high aflatoxin levels. Methods Common CYP3A5 polymorphisms were identified in an African-American population. Subsequently, 288 Gambian subjects were genotyped and CYP3A5 activity predicted using haplotypes of the three variant loci (CYP3A5*3, *6 and *7) associated with decreases in protein expression. CYP3A5 expression was then compared to aflatoxin-albumin (AF-alb) adduct, a biomarker of AFB1 bioactivation; data were also analysed in relation to expression of other aflatoxin-metabolizing enzymes. Results CYP3A5 haplotypes reflecting high CYP3A5 protein expression were associated with increased AF-alb. Compared to individuals with predicted low expression those predicted to express CYP3A5 from one allele displayed 16.1% higher AF-alb (85% CI: -2.5, 38.2, P = 0.083) and homozygous expressers displayed 23.2% higher AF-alb levels (95% CI: -0.01, 52.0, P = 0.051). The effect of the CYP3A5 polymorphism was strongest in individuals with low CYP3A4 activity with a 70.1% increase in AF-alb (95% CI: 11.8, 158.7, P < 0.05) in high compared to low expressers. A similar effect was observed for individuals with null alleles of GSTM1, which conjugates the AFB1-exo-8,9-epoxide to reduced glutathione. Conclusions The CYP3A5 polymorphism is associated with increased levels of the mutagenic AFB1-exo-8,9-epoxide, particularly in individuals with low CYP3A4, and this may modulate individual risk of HCC.
- Genetic polymorphism
- Hepatocellular carcinoma
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)