Kashfi K, McDougall C J, Dannenberg A J
Department of Medicine, New York Hospital-Cornell Medical Center, NY 10021, USA.
Clin Pharmacol Ther. 1995 Dec;58(6):625-30. doi: 10.1016/0009-9236(95)90018-7.
Omeprazole induces CYP1A in the human liver and gut, which has led to concern about possible side effects. The purpose of this study was to compare the effects of omeprazole on phase 1 and phase 2 enzymes in the rat and human. Male rats were treated with intraperitoneal (40 or 80 mg/kg) or oral omeprazole (40 mg/kg) for 5 or 14 days, respectively. The activities and amounts of CYP1A, uridine diphosphate-glucuronosyltransferase, and glutathione transferase were determined in liver and gut. Enzyme activities were also determined in duodenal biopsy specimens from six healthy human volunteers before and after treatment with omeprazole (20 mg/day) for 10 days. Treatment with intraperitoneal omeprazole (40 mg/kg; 80 mg/kg) coinduced uridine diphosphate-glucuronosyltransferase (36%; 66%), glutathione transferase (22%; 50%), and CYP1A (26%; 50%) in rat liver. In rat small intestine, comparable levels of induction were observed for uridine diphosphate-glucuronosyltransferase and glutathione transferase; CYP1A was unaffected. Oral omeprazole had similar effects. Immunoblotting showed corresponding changes in the amounts of these enzymes. Omeprazole increased the activities of CYP1A (19% to 167%; p = 0.014) and uridine diphosphate-glucuronosyltransferase (11% to 68%; p = 0.04) in the duodenal biopsy specimens of all six human volunteers; glutathione transferase was unaffected. Thus, omeprazole coinduced multiple xenobiotic metabolizing enzymes in the rat and human. The pattern of induction differed in the rat and human, consistent with known differences in genetic regulatory elements in the two species.
奥美拉唑可诱导人肝脏和肠道中的CYP1A，这引发了人们对其可能产生的副作用的担忧。本研究的目的是比较奥美拉唑对大鼠和人类1期和2期酶的影响。雄性大鼠分别接受腹腔注射（40或80 mg/kg）或口服奥美拉唑（40 mg/kg），持续5天或14天。测定肝脏和肠道中CYP1A、尿苷二磷酸葡萄糖醛酸转移酶和谷胱甘肽转移酶的活性及含量。还测定了6名健康人类志愿者在接受奥美拉唑（20 mg/天）治疗10天前后十二指肠活检标本中的酶活性。腹腔注射奥美拉唑（40 mg/kg；80 mg/kg）可共同诱导大鼠肝脏中的尿苷二磷酸葡萄糖醛酸转移酶（分别为36%；66%）、谷胱甘肽转移酶（分别为22%；50%）和CYP1A（分别为26%；50%）。在大鼠小肠中，尿苷二磷酸葡萄糖醛酸转移酶和谷胱甘肽转移酶的诱导水平相当；CYP1A未受影响。口服奥美拉唑也有类似作用。免疫印迹显示这些酶的含量有相应变化。奥美拉唑使所有6名人类志愿者十二指肠活检标本中的CYP1A活性增加（19%至167%；p = 0.014）和尿苷二磷酸葡萄糖醛酸转移酶活性增加（11%至68%；p = 0.04）；谷胱甘肽转移酶未受影响。因此，奥美拉唑在大鼠和人类中共同诱导多种外源性物质代谢酶。诱导模式在大鼠和人类中有所不同，这与两个物种已知的基因调控元件差异一致。
