Modification genes for CYP1A2 inducibility among people exposed to polychlorinated biphenyls (PCBs) and dibenzofurans (PCDFs)

• Main Authors: Ping-Wei Huang, 黃柄瑋
• Other Authors: Yueliang Leon Guo
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/85233692810025349024

碩士 === 國立臺灣大學 === 職業醫學與工業衛生研究所 === 97 === Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-furans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) are all important endocrine disrupting chemicals and also persistent organic pollutants. Among them, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to cause most significant health effects in humans. The PCDFs have similar structure and toxicity as PCDDs. Approximately 2000 people were exposed to rice oil contaminated with polychlorinated biphenyls (PCBs) and their heat-degradation products, mainly polychlorinated dibenzofurans (PCDFs) in central Taiwan in 1979. CYP1A2 activity was found to be induced by such exposure in exposed individuals. The aryl hydrocarbon receptor (AhR) pathway was known to be critical in mediating such enzyme induction. Aryl hydrocarbon receptor nuclear translocator (ARNT) and AhR repressor (AhRR) played important roles in transcriptional regulation of AhR. In order to determine whether the ARNT and AhRR polymorphisms are associated with individual inducibility of CYP1A2. We examined the people exposed to PCBs and PCDFs and their community controls, 173 previously participated in a study on CYP1A2 activity as measured by caffeine metabolic rate, which was in turn found to be positively associated with serum 2,3,7,8-TCDD toxic equivalency (TEQ). Genotyping was done for the following SNPs：AhRR(rs2292596)(C/G), ARNT(rs7517566)(A/G), ARNT(rs3820541)(C/G), ARNT(rs3768016)(C/T), and ARNT(rs2228099)(C/G). The allele frequencies of AhRR (rs2292596) were 0.62 for allele C, 0.38 for allele G; those for ARNT (rs7517566) were 0.79 for allele A, and 0.21 for allele G, ARNT (rs3820541) 0.82 for allele C and 0.18 for allele G, ARNT (rs3768016) 0.58 for allele C and 0.42 for allele T, and ARNT (rs2228099) 0.59 for allele C and 0.42 for allele G. At a similar TEQ dose range, those subjects with AhRR GG genotype had the highest induced CYP1A2 activity, followed by those with CG genotype. Those with CC genotypes had lowest inducibility (p<0.05). ARNT(rs3768016) CC genotype had highest inducibility, followed by CT, and TT genotypes. ARNT (rs2228099) GG genotype had highest inducibility, followed by CG, and CC genotypes. We conclude that AhRR and ARNT genotypes might interact with PCBs and PCDFs in cytochrome P450 enzyme induction effects.