Horn Thomas L, Long Lina, Cwik Michael J, Morrissey Robert L, Kapetanovic Izet M, McCormick David L
Life Sciences Group, IIT Research Institute, Chicago, IL 60616, USA.
Chem Biol Interact. 2005 Apr 15;152(2-3):79-99. doi: 10.1016/j.cbi.2005.02.006.
Farnesol demonstrates antitumor activity in several animal models for human cancer and was being considered for development as a cancer chemopreventive agent. This study was performed to characterize the effects of minimally toxic doses of farnesol on the activity of phase I and II drug metabolizing enzymes. CD((R)) rats (20/sex/group) received daily gavage exposure to farnesol doses of 0, 500, or 1000 mg/kg/day for 28 days; 10 rats/sex/group were necropsied at the termination of farnesol exposure; remaining animals were necropsied after a 28-day recovery period. No deaths occurred during the study, and farnesol had no significant effects on body weight, food consumption, clinical signs, or hematology/coagulation parameters. Modest but statistically significant alterations in several clinical chemistry parameters were observed at the termination of farnesol exposure; all clinical pathology effects were reversed during the recovery period. At the termination of dosing, the activities of CYP1A, CYP2A1-3, CYP2B1/2, CYP2C11/12, CYP2E1, CYP3A1/2, CYP4A1-3, CYP19, glutathione reductase, NADPH/quinone oxidoreductase and UDP-glucuronosyltransferase were significantly increased in the livers of farnesol-treated rats; farnesol also increased the activity of glutathione S-transferase in the kidney. The effects of farnesol on hepatic and renal enzymes were reversed during the recovery period. At the end of the dosing period, increases in absolute and relative liver and kidney weights were seen in farnesol-treated rats. These increases may be secondary to induction of drug metabolizing enzymes, since organ weight increases were not associated with histopathologic alterations and were reversed upon discontinuation of farnesol exposure. Administration of farnesol at doses of up to 1000 mg/kg/day induced reversible increases in the activities of several hepatic and renal drug metabolizing enzymes in rats, while inducing only minimal toxicity. It is concluded that non-toxic or minimally toxic doses of farnesol could alter the metabolism, efficacy, and/or toxicity of drugs with which it is co-administered.
法尼醇在多种人类癌症动物模型中显示出抗肿瘤活性，并被考虑开发为癌症化学预防剂。本研究旨在表征最低毒性剂量的法尼醇对I相和II相药物代谢酶活性的影响。CD((R))大鼠（每组雌雄各20只）每天经口灌胃给予0、500或1000 mg/kg/天的法尼醇剂量，持续28天；在法尼醇暴露结束时，每组雌雄各10只大鼠进行尸检；其余动物在28天的恢复期后进行尸检。研究期间无死亡发生，法尼醇对体重、食物摄入量、临床体征或血液学/凝血参数无显著影响。在法尼醇暴露结束时，观察到几个临床化学参数有适度但具有统计学意义的改变；所有临床病理学效应在恢复期均恢复正常。给药结束时，法尼醇处理的大鼠肝脏中CYP1A、CYP2A1 - 3、CYP2B1/2、CYP2C11/12、CYP2E1、CYP3A1/2、CYP4A1 - 3、CYP19、谷胱甘肽还原酶、NADPH/醌氧化还原酶和UDP - 葡萄糖醛酸基转移酶的活性显著增加；法尼醇还增加了肾脏中谷胱甘肽S - 转移酶的活性。法尼醇对肝脏和肾脏酶的影响在恢复期恢复正常。给药期结束时，可以看到法尼醇处理的大鼠肝脏和肾脏的绝对重量和相对重量增加。这些增加可能是药物代谢酶诱导的继发效应，因为器官重量增加与组织病理学改变无关，并且在停止法尼醇暴露后恢复正常。每天给予高达1000 mg/kg/天剂量的法尼醇可诱导大鼠几种肝脏和肾脏药物代谢酶的活性可逆性增加，同时仅诱导最小毒性。结论是，无毒或最低毒性剂量的法尼醇可能会改变与其共同给药药物的代谢、疗效和/或毒性。
