Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa

Pharmacogenetics. 2004 Oct;14(10):691-700. doi: 10.1097/00008571-200410000-00007.

Abstract

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 (95% CI: -2.5, 38.2, P = 0.093) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aflatoxin B1 / analogs & derivatives*
  • Aflatoxin B1 / blood
  • Aflatoxins / blood*
  • Aflatoxins / toxicity
  • Aged
  • Albumins
  • Base Sequence
  • Carcinoma, Hepatocellular / etiology
  • Child
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • DNA / genetics
  • Female
  • Gambia
  • Gene Expression
  • Gene Frequency
  • Genetic Variation
  • Haplotypes
  • Humans
  • Liver Neoplasms / etiology
  • Male
  • Middle Aged
  • Mutagens / metabolism
  • Polymorphism, Genetic*
  • Risk Factors

Substances

  • Aflatoxins
  • Albumins
  • Mutagens
  • aflatoxin-albumin adduct
  • aflatoxin B1-2,3-oxide
  • DNA
  • Cytochrome P-450 Enzyme System
  • Aflatoxin B1
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human