Tao L, Li K, Kramer P M, Pereira M A
Medical College of Ohio, Department of Pathology, Toledo 43614, USA.
Cancer Lett. 1996 Nov 29;108(2):257-61. doi: 10.1016/s0304-3835(96)04451-5.
Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are major metabolites of tetrachloroethylene (PCE) and trichloroethylene (TCE) and are found in chlorinated drinking water. All four chlorinated compounds are liver carcinogens in B6C3F1 mice. It has previously been reported that approximately 20% of hepatic tumors induced by PCE exhibited loss of heterozygosity (LOH) on chromosome 6, suggesting the presence of a tumor suppressor gene. In the current investigation, we determined whether TCA or DCA also induced LOH on chromosome 6. Liver tumors were initiated in 15 day old female B6C3F1 mice with N-methyl-N-nitrosourea (MNU) and promoted with 20 mmol/l DCA or TCA in their drinking water. Twenty-four and thirty-seven liver tumors promoted by DCA and TCA, respectively, were examined for LOH using 4 polymorphic loci on chromosome 6. Ten of 37 (27%) tumors (7 of 27 carcinomas and 3 of 10 adenomas) promoted by TCA exhibited LOH at least for two loci on chromosome 6. All 10 tumors that exhibited LOH, lost the C57BL/6J allele at both the D6mit9 loci, while two also lost at least one of the C3H/HeJ alleles. No LOH on chromosome 6 was observed in the 24 liver tumors promoted by DCA. The LOH on chromosome 6 in TCA but not in DCA-promoted tumors supports it as an active metabolite of PCE and demonstrates different pathogenesis at least for some of the DCA and TCA-promoted liver cancer.
二氯乙酸（DCA）和三氯乙酸（TCA）是四氯乙烯（PCE）和三氯乙烯（TCE）的主要代谢产物，存在于氯化饮用水中。所有这四种氯化化合物在B6C3F1小鼠中都是肝脏致癌物。此前有报道称，PCE诱导的肝肿瘤中约20%在6号染色体上表现出杂合性缺失（LOH），提示存在一个肿瘤抑制基因。在当前研究中，我们确定TCA或DCA是否也会诱导6号染色体上的LOH。用N-甲基-N-亚硝基脲（MNU）启动15日龄雌性B6C3F1小鼠的肝肿瘤，并在其饮用水中加入20 mmol/L的DCA或TCA进行促癌。分别对由DCA和TCA促发的24个和37个肝肿瘤，使用6号染色体上的4个多态性位点检测LOH。由TCA促发的37个肿瘤中有10个（27%）（27个癌中的7个和10个腺瘤中的3个）在6号染色体上至少两个位点表现出LOH。所有表现出LOH的10个肿瘤在D6mit9位点均丢失了C57BL/6J等位基因，而其中两个还至少丢失了一个C3H/HeJ等位基因。在由DCA促发的24个肝肿瘤中未观察到6号染色体上的LOH。TCA促发的肿瘤而非DCA促发的肿瘤中6号染色体上的LOH支持TCA作为PCE的活性代谢产物，并证明至少对于某些DCA和TCA促发的肝癌存在不同的发病机制。
