Environmental Health Science Laboratory, Sumitomo Chemical, Co., Ltd. 1-98, 3-Chome, Kasugade-naka Konohana-ku, Osaka, Japan.
J Agric Food Chem. 2011 May 11;59(9):5001-5. doi: 10.1021/jf200032q. Epub 2011 Apr 8.
To estimate the metabolic profile of trans-permethrin in humans, a comparison of the in vitro metabolism of trans-permethrin in humans and rats was conducted using hepatic microsomes, and cytochrome P450 and UDP-glucuronyltransferase isoforms, which catalyze the metabolism of 3-phenoxybenzyl alcohol (PBalc) and 3-phenoxybenzoic acid (PBacid), respectively. In humans and rats, the major metabolic reaction of trans-permethrin in microsomal incubations was the cleavage of ester linkage to give PBalc, followed by oxidation to 4'-OH-PBalc, 4'-OH-PBacid, and PBacid. As to 4'-hydroxylation of PBalc, several CYPs were able to catalyze the reaction, and CYP2E1 was identified as a predominant isoform. PBacid and its conjugates (glucuronide and glycine) are major urinary metabolites of trans-permethrin in mammals. PBacid is also a metabolite of several pyrethroids, and has been used as a biomarker of human exposure to pyrethroids. Our study indicated that there was no difference in glucuronyltransferase activity of PBacid between humans and rats, and that only UGT1A9 can catalyze the glucuronidation of PBacid among human UGTs. Some UGT1A9 variants are known to have poor glucuronidation activity. From these results, it was assumed that deficiency or polymorphism of UGT1A9 might affect the profile of PBacid and its conjugates in urine collected from persons exposed to trans-permethrin or other pyrethroids. These results are helpful for understanding the metabolism of trans-permethrin in humans and determining methods for quantification of target analytes for assessment of human exposure to trans-permethrin and other pyrethroids that give PBacid and its conjugates as urinary metabolites.
为了估算反式氯菊酯在人体内的代谢特征，我们比较了人肝微粒体和大鼠肝微粒体中外消旋氯菊酯的代谢情况，并用分别催化 3-苯氧基苄醇（PBalc）和 3-苯氧基苯甲酸（PBacid）代谢的细胞色素 P450 和 UDP-葡糖醛酸基转移酶同工酶作为工具。在人及大鼠的微粒体孵育中，反式氯菊酯的主要代谢反应是酯键的裂解，生成 PBalc，然后进一步氧化生成 4'-OH-PBalc、4'-OH-PBacid 和 PBacid。对于 PBalc 的 4'-羟化，几种 CYP 都能催化该反应，CYP2E1 被鉴定为主要同工酶。PBacid 及其结合物（葡糖苷酸和甘氨酸）是哺乳动物中外消旋氯菊酯的主要尿代谢物。PBacid 也是几种拟除虫菊酯的代谢物，已被用作人类接触拟除虫菊酯的生物标志物。我们的研究表明，人类和大鼠的 PBacid 葡糖醛酸基转移酶活性没有差异，且在人类 UGT 中，只有 UGT1A9 能催化 PBacid 的葡糖醛酸化。已知某些 UGT1A9 变体的葡糖醛酸化活性较差。根据这些结果，可以假设 UGT1A9 的缺乏或多态性可能会影响接触反式氯菊酯或其他拟除虫菊酯的个体尿液中 PBacid 及其结合物的特征。这些结果有助于了解反式氯菊酯在人体内的代谢情况，并确定用于评估人类接触反式氯菊酯和其他产生 PBacid 及其结合物作为尿代谢物的拟除虫菊酯的目标分析物的定量方法。
