Don P S, Mukhtar H, Das M, Berger N A, Bickers D R
Department of Dermatology, University Hospitals of Cleveland 44106.
Br J Dermatol. 1989 Feb;120(2):161-71. doi: 10.1111/j.1365-2133.1989.tb07780.x.
The metabolism of benzo(a)pyrene (BP), a ubiquitous environmental carcinogen, and its subsequent binding to DNA, and the repair of UV-induced DNA damage were studied in fibroblasts cultured from the skin of a 61-year-old male who had multiple BCC (greater than 100) on his left upper trunk. Biopsies were obtained and fibroblasts cultured from clinically normal tumour-free skin adjacent to tumour-bearing sites (TBS) and from visibly uninvolved normal skin (UNS) at distant sites. The cultured cells were incubated with [3H]-BP for 24 h and BP metabolism was assessed by HPLC and the formation of BP-diols, quinones and phenols verified. Total BP metabolism was 45% lower in TBS fibroblasts than in UNS fibroblasts. The formation of BP-7,8-diol, the precursor of the carcinogenic end product of BP metabolism, was 53% lower in TBS cells than in UNS cells. Pretreatment of UNS cells with benz(a)anthracene (BA) (x 10(-4) M) did not significantly affect BP metabolite formation whereas BA-treatment of TBS cells resulted in 55% and 76% increases in total BP metabolism and BP-7,8-diol formation, respectively. Treatment of TBS cells with BA also caused a substantial increase (95%) in BP-DNA adduct formation. Whereas DNA-binding in UNS cells was unaffected by this treatment. In response to irradiation with 2J/m2 UVC, total DNA repair was similar in both cell types; on alkaline elution it appeared that the TBS cells were more efficient in repairing UV-induced DNA strand breaks. These results suggest that BP metabolism and repair of DNA are altered in TBS cells and that patients with this type of metabolic profile may be at higher risk of the development of cutaneous neoplasms. It is also possible that fibroblasts from tumour bearing skin undergo some as yet unexplained alteration in carcinogen metabolism as a consequence of the induction of neoplasia.
研究了苯并(a)芘（BP，一种普遍存在的环境致癌物）的代谢、其与DNA的后续结合以及紫外线诱导的DNA损伤修复情况。研究对象为一名61岁男性，其左上躯干有多处基底细胞癌（超过100处），从其皮肤培养成纤维细胞进行研究。获取活检样本，从肿瘤部位（TBS）相邻的临床正常、无肿瘤的皮肤以及远处明显未受累的正常皮肤（UNS）培养成纤维细胞。将培养的细胞与[3H]-BP孵育24小时，通过高效液相色谱法评估BP代谢，并验证BP -二醇、醌和酚的形成。TBS成纤维细胞中的总BP代谢比UNS成纤维细胞低45%。BP代谢致癌终产物的前体BP - 7,8 -二醇的形成，TBS细胞比UNS细胞低53%。用苯并(a)蒽（BA）（10(-4) M）预处理UNS细胞对BP代谢物形成没有显著影响，而用BA处理TBS细胞分别使总BP代谢和BP - 7,8 -二醇形成增加了55%和76%。用BA处理TBS细胞还导致BP - DNA加合物形成大幅增加（95%）。而这种处理对UNS细胞中的DNA结合没有影响。用2J/m2的UVC照射后，两种细胞类型的总DNA修复相似；在碱性洗脱时，似乎TBS细胞在修复紫外线诱导的DNA链断裂方面更有效。这些结果表明，TBS细胞中的BP代谢和DNA修复发生了改变，具有这种代谢特征的患者可能患皮肤肿瘤的风险更高。也有可能是肿瘤皮肤中的成纤维细胞由于肿瘤形成的诱导，在致癌物代谢方面发生了一些尚未解释清楚的改变。
