多氯聯苯/夫喃中毒者體內CYP1A2酵素誘導性修飾基因研究

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

黃柄瑋(Ping-Wei Huang)

指導教授 ： 郭育良

共同指導教授 ： 陳保中(Pau-Chung Chen)

國立臺灣大學/公共衛生學院/職業醫學與工業衛生研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.01832

摘要

多氯聯苯（Polychlorinated biphenyls, PCBs）、多氯夫喃（polychlorinated dibenzo-p-furans, PCDFs）和多氯戴奧辛（dibenzo-p-dioxins, PCDDs）皆是環境中重要的環境荷爾蒙，而且屬於一種持久性有機污染物（persistent organic pollutants, POPs），其同源物 (congeners)中，以2,3,7,8-TCDD的毒性為最強，健康方面的危害包括致癌性、肝毒性、免疫毒性、生殖系統毒性、皮膚毒性等。
1979年，台灣中部地區約2000人食用受多氯聯苯以及其熱分解產物多氯夫喃汙染之米糠油。而人體內CYP1A2酵素的活性會受到暴露程度而有不同的誘導程度。而已知芳香烴受體 (aryl hydrocarbon receptor, AhR) 途徑為此酵素誘導調控的關鍵；而aryl hydrocarbon receptor nuclear translocator (AhR) 與 Aryl hydrocarbon receptor repressor (AhRR) 也是轉錄過程中的重要因子。
為了了解ARNT與AhRR基因多型性與CYP1A2誘導性 (inducibility) 是否有關連，此研究中，我們對於173位暴露多氯聯苯與多氯夫喃的對象，以及其社區對照組，進行了以咖啡因代謝速率做為CYP1A2酵素活性指標的試驗，發現其與血清之中 2,3,7,8-TCDD毒性當量 (toxic equivalency, TEQ) 有正相關。
對ARNT與AhRR基因，進行下列單一核苷酸多型性基因型 (single nucleotide polymorphism, SNP)分析，一個AhRR基因SNP，AhRR (rs2292596)(C/G), 與四個ARNT基因，分別是ARNT(rs7517566)(A/G)、 ARNT(rs3820541)(C/G)、ARNT(rs3768016)(C/T)以及ARNT(rs2228099)(C/G)。
分析結果，對偶基因頻率 (allele frequency)結果為，AhRR(rs2292596)的C型對偶基因頻率為0.62，G型0.38 ，四個ARNT基因，分別是ARNT(rs7517566)的A型對偶基因頻率為0.79，G型為0.21，ARNT(rs3820541)的C型對偶基因頻率為0.82，C型為0.18，ARNT(rs3768016)的C型對偶基因頻率為0.58，T型為0.42以及ARNT(rs2228099)的C型為0.59，G型為0.42。在相近的毒性當量之下，AhRR SNP基因為GG型的基因型者，CYP1A2的誘發程度高於AhRR SNP基因型為CG型者，而AhRR(rs2292596)基因型為CC型者，CYP1A2酵素的誘發程度為三個基因型中最低(p<0.05)。在ARNT(rs3768016)基因上的CYP1A2誘發程度比較，CC型的基因型較CT型與TT型基因型有較高的誘發程度。ARNT (rs2228099)基因中，基因型為GG者，誘發程度高於CG型與CC型。我們推論AhRR與ARNT基因的基因多型性，可能影響PCBs 與PCDFs在cytochrome P450酵素上的誘發程度。

關鍵字

多氯聯苯 ； 多氯夫喃 ； 基因多型性 ； 芳香烴基受體 ； 芳香烴核轉位蛋白 ； 芳香烴基受體抑制物 ； 細胞色素P4501A2(CYP1A2)

並列摘要

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.

並列關鍵字

polychlorinated biphenyls (PCBs) ； polychlorinated dibenzofurans (PCDFs) ； genetic polymorphism ； aryl hydrocarbon receptor (AhR) ； AhR nuclear translocator (ARNT) ； AhR repressor (AhRR) ； cytochrome P4501A2(CYP1A2)

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