Wang J S, Shen X, He X, Zhu Y R, Zhang B C, Wang J B, Qian G S, Kuang S Y, Zarba A, Egner P A, Jacobson L P, Muñoz A, Helzlsouer K J, Groopman J D, Kensler T W
Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, MD, USA.
J Natl Cancer Inst. 1999 Feb 17;91(4):347-54. doi: 10.1093/jnci/91.4.347.
Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of foods contaminated with aflatoxins, which require metabolic activation to become carcinogenic. In a randomized, placebo-controlled, double-blind phase IIa chemoprevention trial, we tested oltipraz, an antischistosomal drug that has been shown to be a potent and effective inhibitor of aflatoxin-induced hepatocarcinogenesis in animal models.
In 1995, 234 adults from Qidong were enrolled. Healthy eligible individuals were randomly assigned to receive by mouth 125 mg oltipraz daily, 500 mg oltipraz weekly, or a placebo. Sequential immunoaffinity chromatography and liquid chromatography coupled to mass spectrometry or to fluorescence detection were used to identify and quantify phase 1 and phase 2 metabolites of aflatoxin B1 in the urine of study participants. Reported P values are two-sided.
One month of weekly administration of 500 mg oltipraz led to a 51% decrease in median levels of the phase 1 metabolite aflatoxin M1 excreted in urine compared with administration of a placebo (P = .030), but it had no effect on levels of a phase 2 metabolite, aflatoxin-mercapturic acid (P = .871). By contrast, daily intervention with 125 mg oltipraz led to a 2.6-fold increase in median aflatoxin-mercapturic acid excretion (P = .017) but had no effect on excreted aflatoxin M1 levels (P = .682).
Intermittent, high-dose oltipraz inhibited phase 1 activation of aflatoxins, and sustained low-dose oltipraz increased phase 2 conjugation of aflatoxin, yielding higher levels of aflatoxin-mercapturic acid. While both mechanisms can contribute to protection, this study highlights the feasibility of inducing phase 2 enzymes as a chemopreventive strategy in humans.
中华人民共和国启东市居民患肝细胞癌的风险很高，部分原因是食用了被黄曲霉毒素污染的食物，黄曲霉毒素需要代谢激活才能致癌。在一项随机、安慰剂对照、双盲IIa期化学预防试验中，我们测试了奥替普拉，一种抗血吸虫病药物，在动物模型中已被证明是黄曲霉毒素诱导肝癌发生的有效抑制剂。
1995年，招募了234名来自启东的成年人。符合条件的健康个体被随机分配，每天口服125毫克奥替普拉、每周口服500毫克奥替普拉或服用安慰剂。采用顺序免疫亲和色谱法和液相色谱-质谱联用或荧光检测法，对研究参与者尿液中黄曲霉毒素B1的1期和2期代谢产物进行鉴定和定量。报告的P值为双侧。
与服用安慰剂相比，每周服用500毫克奥替普拉一个月导致尿液中排出的1期代谢产物黄曲霉毒素M1的中位数水平降低了51%（P = 0.030），但对2期代谢产物黄曲霉毒素-巯基尿酸的水平没有影响（P = 0.871）。相比之下, 每天服用125毫克奥替普拉导致黄曲霉毒素-巯基尿酸排泄中位数增加2.6倍（P = 0.017），但对排出的黄曲霉毒素M1水平没有影响（P = 0.682）。
间歇性高剂量奥替普拉抑制黄曲霉毒素的1期激活，持续低剂量奥替普拉增加黄曲霉毒素的2期结合，产生更高水平的黄曲霉毒素-巯基尿酸。虽然这两种机制都有助于提供保护，但本研究强调了诱导2期酶作为人类化学预防策略的可行性。
