Genetic susceptibility to dioxin-like chemicals' induction of cytochrome P4501A2 in the human adult linked to specific AhRR polymorphism

摘要

Background: Dioxin-like chemicals are known to exert their effect by binding to aryl hydrocarbon receptor (AhR), forming complexes with aryl hydrocarbon nuclear translocator (ARNT), and binding to dioxin responsive elements (DREs) in promoter region to regulate the transcription of specific genes. In a previous study of the Yucheng cohort of humans who were exposed to high toxic levels of dioxin-like chemicals (PCDFs and PCBs), we reported marked induction of cytochrome P450 1A2 (CYP1A2) activity and this induction was an excellent biomarker of the exposure and adverse human health effects seen in the Yucheng cohort. Objectives: The goal of this study was to determine the relationship between inducibility of CYP1A2 and genetic polymorphisms of AhR, ARNT, and AhRR in human. Methods: The Yucheng victims who completed blood sample collecting in 1994-1995 for serum concentrations of PCB, PCDF, and PCDD congeners, and also completed the caffeine breath tests for CYP1A2 activity were identified. From the collected blood samples, six single nucleotide polymorphisms were selected for genotyping, including AhR (rs2066853), AhRR (rs2292596), ARNT (rs7517566), ARNT (rs3820541), ARNT (rs3768016), and ARNT (rs2228099). Results: AhRR (rs2292596) polymorphism was significantly related to CYP1A2 inducibility (p = 0.01). A linear trend test was observed between people with AhRR (rs2292596) GC, GC, and CC genotype (p = 0.0014). Conclusion: Overall, AhRR (rs2292596) genotypes predict the inducibility of CYP1A2 in people highly exposed to toxic dioxin-like chemicals. Future studies and analysis will determine to what degree these polymorphisms can predict a human's susceptibility to dioxin-related adverse human health effects.