Martelli A, Mattioli F, Mereto E, Brambilla Campart G, Sini D, Bergamaschi G, Brambilla G
Department of Internal Medicine, University of Genoa, Italy.
Toxicology. 1998 Sep 1;130(1):29-41. doi: 10.1016/s0300-483x(98)00101-2.
Omeprazole, a proton pump inhibitor of wide use in the treatment of gastric acid-related disorders, was evaluated for its genotoxic effects in both rat and human cultured cells and in the intact rat. DNA repair synthesis, as revealed by autoradiography, was detected in primary cultures of metabolically competent rat hepatocytes exposed to concentrations ranging from 10 to 100 mg/l, but the responses cannot be considered as clearly positive. Under the same experimental conditions any significant evidence of DNA repair was absent in primary hepatocytes from two human donors. At the same concentrations a modest but dose-related increase of micronucleated cells, that reached the level of statistical significance at 33 mg/l, was present in primary rat hepatocytes and in one of two human donors. In human lymphocytes exposed to subtoxic concentrations ranging from 0.78 to 12.5 mg/l a reproducible concentration dependent clastogenic effect was absent. In partially hepatectomized female rats treated with a single p.o. dose of 1000 mg/kg, the frequency of micronucleated cells was 5.2-fold higher than in controls in the liver, but only 2.0-fold higher in polychromatic erythrocytes of the bone marrow. In rats of the same sex given azoxymethane as initiator of colon carcinogenesis the oral administration for 8 successive weeks of 10 mg/kg omeprazole on alternate days increased the response to azoxymethane, as indicated by the occurrence in colon mucosa of a modest but statistically significant increase in both the average number and size of aberrant crypt foci. Taken as a whole, our results suggest that omeprazole behaves as a weak genotoxic agent for the rat liver. Reliable information about the potential genotoxic risk to humans requires further studies on primary cells from a wide number of donors.
奥美拉唑是一种广泛用于治疗胃酸相关疾病的质子泵抑制剂，已在大鼠和人类培养细胞以及完整大鼠中评估了其遗传毒性作用。通过放射自显影显示，在暴露于浓度范围为10至100mg/l的具有代谢能力的大鼠原代肝细胞培养物中检测到DNA修复合成，但这些反应不能被视为明确阳性。在相同实验条件下，来自两名人类供体的原代肝细胞中没有任何明显的DNA修复证据。在相同浓度下，原代大鼠肝细胞和两名人类供体之一中出现了微核细胞的适度但与剂量相关的增加，在33mg/l时达到统计学显著水平。在暴露于0.78至12.5mg/l亚毒性浓度的人类淋巴细胞中，未出现可重复的浓度依赖性致断裂效应。在用1000mg/kg单次口服剂量治疗的部分肝切除雌性大鼠中，肝脏中微核细胞的频率比对照组高5.2倍，但骨髓多染红细胞中仅高2.0倍。在给予偶氮甲烷作为结肠癌发生启动剂的同性大鼠中，每隔一天口服10mg/kg奥美拉唑连续8周增加了对偶氮甲烷的反应，结肠黏膜中异常隐窝灶的平均数量和大小均有适度但统计学上显著的增加表明了这一点。总体而言，我们的结果表明奥美拉唑对大鼠肝脏表现为一种弱遗传毒性剂。关于对人类潜在遗传毒性风险的可靠信息需要对来自大量供体的原代细胞进行进一步研究。
