Gustafson D L, Long M E, Thomas R S, Benjamin S A, Yang R S
Center for Environmental Toxicology and Technology, Department of Environmental Health, Colorado State University, Fort Collins 80523-1680, USA.
Toxicol Sci. 2000 Feb;53(2):245-52. doi: 10.1093/toxsci/53.2.245.
Of the twelve different chlorobenzene isomers, a thorough evaluation of carcinogenicity has only been assessed on monochlorobenzene, 1,2-, and 1,4-dichlorobenzene, and hexachlorobenzene. In the studies presented here, we measured the ability of 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TeCB), pentachlorobenzene (PeCB), and hexachlorobenzene (HCB) to promote glutathione S-transferase pi (GSTP1-1) positive preneoplastic foci formation in rat liver, following diethylnitrosamine (DEN) initiation. The results from these studies show that TeCB, PeCB, and HCB all promote the formation of GSTP1-1 positive foci and that DCB does not. The numbers and area of foci were greatest following HCB promotion, and TeCB and PeCB were approximately equal in their promoting ability. Levels of hepatic CYP1A2, CYP2B1/2, non-focal GSTP1-1, and c-fos were measured in response to treatment with the 4 chlorobenzene isomers, as were reduced glutathione (GSH) and oxidized glutathione (GSSG) levels. Results from these studies show that induction of CYP1A2 and CYP2B1/2 have correlation with both the presence and degree of GSTP1-1 foci promotion by the 4 chlorobenzenes. Alterations in GSH and GSSG levels were similar in PeCB- and TeCB-treated animals in that GSSG levels were significantly decreased, whereas HCB and DCB did not have this effect, although HCB treatment led to a significant increase in GSH levels. We conclude that induction of CYP1A2 or CYP2B1/2 by chlorobenzene isomers may indicate promotional ability, and that this property might be exploited to predict the hepatocarcinogenicity of other chlorobenzene isomers.
在十二种不同的氯苯异构体中，仅对一氯苯、1,2 - 二氯苯、1,4 - 二氯苯和六氯苯进行了全面的致癌性评估。在本文所述的研究中，我们测定了1,4 - 二氯苯（DCB）、1,2,4,5 - 四氯苯（TeCB）、五氯苯（PeCB）和六氯苯（HCB）在二乙基亚硝胺（DEN）启动后促进大鼠肝脏中谷胱甘肽S - 转移酶pi（GSTP1 - 1）阳性癌前病灶形成的能力。这些研究结果表明，TeCB、PeCB和HCB均能促进GSTP1 - 1阳性病灶的形成，而DCB则不能。HCB促进后病灶的数量和面积最大，TeCB和PeCB的促进能力大致相当。测定了肝脏中CYP1A2、CYP2B1/2、非病灶性GSTP1 - 1和c - fos的水平，以响应这4种氯苯异构体的处理，同时还测定了还原型谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）的水平。这些研究结果表明，CYP1A2和CYP2B1/2的诱导与这4种氯苯促进GSTP1 - 1病灶形成的存在和程度均相关。PeCB和TeCB处理的动物中GSH和GSSG水平的变化相似，即GSSG水平显著降低，而HCB和DCB没有这种作用，尽管HCB处理导致GSH水平显著升高。我们得出结论，氯苯异构体对CYP1A2或CYP2B1/2的诱导可能表明其促进能力，并且可以利用这一特性来预测其他氯苯异构体的肝致癌性。
