Fitzgerald J E, Sanyer J L, Schardein J L, Lake R S, McGuire E J, de la Iglesia F A
J Natl Cancer Inst. 1981 Nov;67(5):1105-16.
Gemfibrozil, a novel hypolipidemic agent identified chemically as 2,2-dimethyl-5-(2,5-xylyoxy) valeric acid, was evaluated for mutagenic potential in in vitro assays with Salmonella typhimurium. For evaluation of tumorigenic potential, gemfibrozil was administered in the diet (0.30, and 300 mg gemfibrozil/kg) to groups of noninbred CD-1 mice (72/sex) and noninbred CD rats (50/sex) for 78 and 104 weeks, respectively. In the bacterial mutagenesis assays, between 100 and 2,500 microgram gemfibrozil/plate failed to induce a significant increase in revertant bacterial colonies. Neither was a mutagenic response in bacterial assays induced at concentrations up to 300 microgram of five in vivo metabolites of gemifibrozil isolated from rat urine/plate. In mice, gemfibrozil did not significantly increase the frequency or the mean latency period of tumors. In rats, the statistically significant increases in hepatocellular tumors and interstitial cell tumors of the testes were dose related. Adrenal medullary and pancreatic acinar tumors were increased in male rats but were inversely dose related. Under the conditions of this assay, gemfibrozil did not elicit a tumorigenic potential in mice and female rats. In male rats and related to the hepatocellular tumor response, the peroxisome proliferation seen did not occur in humans chronically administered hypolipidemics.
吉非贝齐是一种经化学鉴定为2,2 - 二甲基 - 5 - (2,5 - 二甲苯氧基)戊酸的新型降血脂药物，我们用鼠伤寒沙门氏菌进行体外试验评估了其致突变潜力。为评估其致癌潜力，将吉非贝齐添加到饲料中（0.30和300毫克吉非贝齐/千克），分别喂给非近交系CD - 1小鼠（每组72只，雌雄各半）和非近交系CD大鼠（每组50只，雌雄各半）78周和104周。在细菌诱变试验中，每平皿100至2500微克吉非贝齐未能诱导回复突变细菌菌落显著增加。从大鼠尿液中分离出的吉非贝齐的五种体内代谢物，每平皿浓度高达300微克时也未在细菌试验中诱导出诱变反应。在小鼠中，吉非贝齐未显著增加肿瘤的发生率或平均潜伏期。在大鼠中，肝细胞肿瘤和睾丸间质细胞瘤的统计学显著增加与剂量相关。雄性大鼠的肾上腺髓质瘤和胰腺腺泡瘤增加，但与剂量呈负相关。在本试验条件下，吉非贝齐在小鼠和雌性大鼠中未引发致癌潜力。在雄性大鼠中，与肝细胞肿瘤反应相关的过氧化物酶体增殖在长期服用降血脂药物的人类中未出现。
