MECHANISM FOR SPECIES-SPECIFIC INDUCTION OF LEYDIG-CELL TUMORS IN RATS BY LANSOPRAZOLE

Lansoprazole is a substituted benzimidazole which inhibits gastric aci d secretion by inhibiting the hydrogen-potassium ATPase (proton pump) in the parietal cell. The finding of Leydig cell hyperplasia and Leydi g cell tumors in 2-year oral studies in Sprague-Dawley rats but not in CD-1 mice prompted investigative studies to determine the mechanism f or the Leydig cell changes. hCG challenge studies in Sprague-Dawley ra ts revealed decreased testosterone responsiveness in rats treated oral ly for 1 or 2 weeks with lansoprazole. After 4 weeks of daily oral tre atment increases in serum LH and decreases in serum testosterone were detected within a few hours after dosing. In a study where 9-month-old male F344 rats were given testosterone supplementation via Silastic i mplants and then treated with lansoprazole for 6 months, a high incide nce of Leydig cell tumors was seen in lansoprazole-treated, unsuppleme nted rats, whereas no Leydig cell tumors were seen in testosterone sup plemented rats. This implied that reduction of the normal feedback inh ibition at the level of the hypothalamus and/or pituitary due to reduc ed testosterone levels, thus giving rise to elevated levels of LH, was involved in the induction of Leydig cell tumors by lansoprazole. In v itro studies with Leydig cells from rats using various stimulators and precursors of testosterone biosynthesis demonstrated that the most se nsitive site for inhibition of testosterone synthesis by lansoprazole is the transport of cholesterol to the cholesterol side chain cleavage enzyme, The IC50s for inhibition of LH or hCG-stimulated testosterone synthesis in Leydig cells from rats, mice, and monkeys were 11-12, 8, and 27.4 mu g/ml, respectively, In vitro studies with metabolites of lansoprazole revealed that three metabolites were more potent inhibito rs of testosterone synthesis than the parent drug, two of them being a t least 10 times more potent. These metabolites are present in rats at substantial levels but are undetectable in humans. The lack of induct ion of Leydig cell tumors in mice, lower sensitivity of primate Leydig cells, and the absence of testosterone synthesis-inhibiting metabolit es in man suggest that Leydig cell tumors found in rats represent a sp ecies-specific sensitivity and does not imply a risk for clinical use in man. (C) 1995 Society of Toxicology.