Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: relative disposition of chloral hydrate to trichloroacetate and trichloroethanol.
Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: relative disposition of chloral hydrate to trichloroacetate and trichloroethanol.
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DOI：
10.1289/ehp.9047
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发表时间：
2006-08
影响因子：
10.4
通讯作者：
Hoel DG
中科院分区：
文献类型：
--
作者：
Bronley-DeLancey A;McMillan DC;McMillan JM;Jollow DJ;Mohr LC;Hoel DG
三氯乙烯（TCE）是一种可疑的人类致癌物，也是一种常见的地下水污染物。水合氯醛（CH）是三氯乙烯在肝脏中通过细胞色素P450 2 E1形成的主要代谢产物。CH通过醛脱氢酶（ALDH）代谢为致癌物质三氯乙酸（TCA），通过醇脱氢酶（ADH）代谢为非致癌代谢物三氯乙醇（TCOH）。ALDH和ADH在人类中是多态性的，并且已知这些多态性影响乙醇的消除。因此，CH代谢的多态性可能会产生比预期更大的TCA形成亚群，TCE暴露后肝肿瘤风险增加。目前的研究进行，以确定使用市售的，低温保存的人肝细胞，同时确定CH代谢和ALDH/ADH基因型的动力学的可行性。检查了13份人肝细胞样本。对11个ADH和12个ALDH测定得到线性倒数图。TCOH和TCA形成的Vmax值存在较大的个体间差异。在这个有限的样本量内，ADH/ALDH基因型之间没有明显的相关性。尽管Vmax值个体之间的差异很大，处置CH到两个竞争的途径是相对恒定的。这些数据支持使用冷冻保存的人肝细胞作为实验系统，以产生代谢和基因组信息，用于纳入TCE癌症风险评估模型。数据进行了讨论，关于细胞因素，基因型以外，可能有助于观察到的变异代谢CH在人类肝脏。
Trichloroethylene (TCE) is a suspected human carcinogen and a common ground-water contaminant. Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH is metabolized to the hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenase (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metabolism and ALDH/ADH genotype. Thirteen human hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. There was large interindividual variation in the Vmax values for both TCOH and TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent. Despite the large variation in Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. These data support the use of cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assessment models. The data are discussed with regard to cellular factors, other than genotype, that may contribute to the observed variability in metabolism of CH in human liver.
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影响因子：
10.4
作者：
Bull RJ
通讯作者：
Bull RJ
影响因子：
4.1
作者：
DALZIEL, K;DICKINSON, FM
通讯作者：
DICKINSON, FM
影响因子：
2.9
作者：
BURNELL, JC;LI, TK;BOSRON, WF
通讯作者：
BOSRON, WF
影响因子：
2.8
作者：
EHRIG, T;BOSRON, WF;LI, TK
通讯作者：
LI, TK
DOI：
10.1016/s0378-4347(99)00282-0
发表时间：
1999-09-10
期刊：
JOURNAL OF CHROMATOGRAPHY B
影响因子：
--
作者：
Muralidhara, S;Bruckner, JV
通讯作者：
Bruckner, JV