Cantoreggi S, Lutz W K
Swiss Federal Institute of Technology, Schwerzenbach.
Carcinogenesis. 1992 Feb;13(2):193-7. doi: 10.1093/carcin/13.2.193.
Styrene-7,8-oxide (SO), the main intermediate metabolite of styrene, induces hyperkeratosis and tumors in the forestomach of rats and mice upon chronic administration by gavage. The aim of this study was to investigate whether DNA binding could be responsible for the carcinogenic effect observed. [7-3H]SO was administered by oral gavage in corn oil to male CD rats at two dose levels (1.65 or 240 mg/kg). After 4 or 24 h, forestomach, glandular stomach and liver were excised, DNA was isolated and its radioactivity determined. At the 4 h time point, the DNA radioactivity was below the limit of detection in the forestomach and the liver. Expressed in the units of the covalent binding index, CBI = (mumol adduct/mol DNA nucleotide)/(mmol chemical administered/kg body wt), the DNA-binding potency was below 2.6 and 2.0 respectively. In the glandular stomach at 4 h, and in most 24 h samples, DNA was slightly radiolabeled. Enzymatic degradation of the DNA and separation by HPLC of the normal nucleotides showed that the DNA radioactivity represented biosynthetic incorporation of radiolabel into newly synthesized DNA. The limit of detection of DNA adducts in the glandular stomach was 1.0. In a second experiment, [7-3H]SO was administered by i.p. injection to male B6C3F1 mice. Liver DNA was analyzed after 2 h. No radioactivity was detectable at a limit of detection of CBI less than 0.6. In agreement with the relatively long half-life of SO in animals, the chemical reactivity of SO appears to be too low to result in a detectable production of DNA adducts in an in vivo situation. Upon comparison with the DNA-binding of other carcinogens, a purely genotoxic mechanism of tumorigenic action of SO is unlikely. The observed tumorigenic potency in the forestomach could be the result of strong tumor promotion by high-dose cytotoxicity followed by regenerative hyperplasia.
苯乙烯-7,8-氧化物（SO）是苯乙烯的主要中间代谢产物，通过灌胃长期给药可在大鼠和小鼠的前胃诱发角化过度和肿瘤。本研究的目的是调查DNA结合是否可能是观察到的致癌作用的原因。将[7-³H]SO以玉米油为溶剂经口灌胃给予雄性CD大鼠，剂量为两个水平（1.65或240mg/kg）。4或24小时后，切除前胃、腺胃和肝脏，分离DNA并测定其放射性。在4小时时间点，前胃和肝脏中的DNA放射性低于检测限。以共价结合指数（CBI =（μmol加合物/mol DNA核苷酸）/（mmol化学物质给药/kg体重））表示，DNA结合能力分别低于2.6和2.0。在4小时时的腺胃以及大多数24小时的样本中，DNA有轻微放射性标记。DNA的酶促降解以及正常核苷酸通过高效液相色谱法的分离表明，DNA放射性代表放射性标记物生物合成掺入新合成的DNA中。腺胃中DNA加合物的检测限为1.0。在第二个实验中，将[7-³H]SO经腹腔注射给予雄性B6C3F1小鼠。2小时后分析肝脏DNA。在CBI检测限小于0.6时未检测到放射性。与SO在动物体内相对较长的半衰期一致，SO的化学反应性似乎太低，以至于在体内情况下无法导致可检测到的DNA加合物产生。与其他致癌物的DNA结合情况相比，SO致瘤作用的纯基因毒性机制不太可能。在前胃中观察到的致瘤能力可能是高剂量细胞毒性后再生性增生导致的强烈肿瘤促进作用的结果。
