Swenberg J A, Fedtke N, Ciroussel F, Barbin A, Bartsch H
University of North Carolina, Chapel Hill 27599.
Carcinogenesis. 1992 Apr;13(4):727-9. doi: 10.1093/carcin/13.4.727.
Preweanling rats were exposed to 600 p.p.m. (4h/day) of the human carcinogen vinyl chloride for 5 days to determine the molecular dosimetry of DNA adducts in liver, lung and kidney. 7-(2'-Oxoethyl)guanine (7OEG) was the major DNA adduct detected, representing approximately 98% of all adducts. N2,3-Ethenoguanine (epsilon G) and 3,N4-etheno-2'-deoxycytidine (epsilon dC) were present at approximately 1% of the 7OEG concentration, while 1,N6-etheno-2'-deoxyadenosine was present in even lower concentrations. Liver had 3- to 8-fold higher amounts of the DNA adducts than lung and kidney. The persistence of all four adducts was determined at 3, 7 and 14 days post-exposure. Whereas 7OEG had a t 1/2 of -62 h, all three etheno adducts were highly persistent. After accounting for dilution due to growth-related cell proliferation, epsilon G had a t 1/2 of approximately 30 days, while epsilon dC and epsilon dA were not repaired. These data suggest that these cyclic adducts are poorly recognized by liver DNA repair enzymes and have the potential for accumulation upon chronic exposure. This, coupled with the known miscoding properties of the ethenobases, provides a strong rational for examining their role in vinyl chloride-induced cancer and their utility as biomarkers of exposure.
将断奶前的大鼠暴露于600 ppm（每天4小时）的人类致癌物氯乙烯中5天，以确定肝脏、肺和肾脏中DNA加合物的分子剂量学。7-(2'-氧代乙基)鸟嘌呤(7OEG)是检测到的主要DNA加合物，约占所有加合物的98%。N2,3-乙烯基鸟嘌呤(εG)和3,N4-乙烯基-2'-脱氧胞苷(εdC)的含量约为7OEG浓度的1%，而1,N6-乙烯基-2'-脱氧腺苷的含量更低。肝脏中的DNA加合物含量比肺和肾脏高3至8倍。在暴露后3、7和14天测定了所有四种加合物的持久性。7OEG的半衰期为-62小时，而所有三种乙烯基加合物都具有高度持久性。在考虑了与生长相关的细胞增殖引起的稀释后，εG的半衰期约为30天，而εdC和εdA未被修复。这些数据表明，这些环状加合物很难被肝脏DNA修复酶识别，并且在长期暴露时有积累的可能性。这与乙烯基碱基已知的错配特性相结合，为研究它们在氯乙烯诱导的癌症中的作用及其作为暴露生物标志物的效用提供了有力的依据。
