Titre du document / Document title

Mechanism for species-specific induction of leydig cell tumors in rats by lansoprazole

Auteur(s) / Author(s)

FORT F. L. ⁽¹⁾ ; MIYAJIMA H. ; ANDO T. ; SUZUKI T. ; YAMAMOTO M. ; HAMASHIMA T. ; SATO S. ; KITAZAKI T. ; MAHONY M. C. ; HODGEN G. D. ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Abbott Laboratories, Abbott Park IL 60064, ETATS-UNIS

Résumé / Abstract

Lansoprazole is a substituted benzimidazole which inhibits gastric acid secretion by inhibiting the hydrogen-potassium ATPase (proton pump) in the parietal cell. The finding of Leydig cell hyperplasia and Leydig cell tumors in 2-year oral studies in Sprague-Dawley rats but not in CD-1 mice prompted investigative studies to determine the mechanism for the Leydig cell changes. hCG challenge studies in Sprague-Dawley rats revealed decreased testosterone responsiveness in rats treated orally for 1 or 2 weeks with lansoprazole. After 4 weeks of daily oral treatment 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 implants and then treated with lansoprazole for 6 months, a high incidence of Leydig cell tumors was seen in lansoprazole-treated, unsupplemented rats, whereas no Leydig cell tumors were seen in testosterone supplemented rats. This implied that reduction of the normal feedback inhibition at the level of the hypothalamus and/or pituitary due to reduced testosterone levels, thus giving rise to elevated levels of LH, was involved in the induction of Leydig cell tumors by lansoprazole. In vitro studies with Leydig cells from rats using various stimulators and precursors of testosterone biosynthesis demonstrated that the most sensitive 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 μg/ml, respectively. In vitro studies with metabolites of lansoprazole revealed that three metabolites were more potent inhibitors of testosterone synthesis than the parent drug, two of them being at least 10 times more potent. These metabolites are present in rats at substantial levels but are undetectable in humans. The lack of induction of Leydig cell tumors in mice, lower sensitivity of primate Leydig cells, and the absence of testosterone synthesis-inhibiting metabolites in man suggest that Leydig cell tumors found in rats represent a species-specific sensitivity and does not imply a risk for clinical use in man. © 1995 Society of Toxicology.

Revue / Journal Title

Fundamental and applied toxicology   ISSN 0272-0590   CODEN FAATDF 

Source / Source

1995, vol. 26, n^o2, pp. 191-202 (1 p.1/4)

Langue / Language

Anglais

Editeur / Publisher

Academic Press, San Diego, CA, ETATS-UNIS  (1981-1997) (Revue)

Mots-clés anglais / English Keywords

In vitro ; Interspecific comparison ; Enzyme inhibitor ; H⁺/K⁺-exchanging ATPase ; Toxicity ; Carcinogen ; Rat ; Mouse ; Animal ; Species specificity ; Malignant tumor ; Leydig cell ; Oral administration ; Chronic ; Pituitary gland ; Benzimidazole derivatives ; In vivo ; Testicle ; Hydrolases ; Enzyme ; Rodentia ; Mammalia ; Vertebrata ; Male genital diseases ; Endocrinopathy ;

Mots-clés français / French Keywords

Lansoprazole ; In vitro ; Comparaison interspécifique ; Inhibiteur enzyme ; H⁺/K⁺-exchanging ATPase ; Toxicité ; Carcinogène ; Rat ; Souris ; Animal ; Spécificité espèce ; Tumeur maligne ; Cellule Leydig ; Voie orale ; Chronique ; Hypophyse ; Benzimidazole dérivé ; In vivo ; Testicule ; Hydrolases ; Enzyme ; Rodentia ; Mammalia ; Vertebrata ; Appareil génital mâle pathologie ; Endocrinopathie ;

Mots-clés espagnols / Spanish Keywords

In vitro ; Comparación interespecífica ; Inhibidor enzima ; H⁺/K⁺-exchanging ATPase ; Toxicidad ; Carcinógeno ; Rata ; Ratón ; Animal ; Especificidad especie ; Tumor maligno ; Célula Leydig ; Vía oral ; Crónico ; Hipófisis ; Benzimidazol derivado ; In vivo ; Testículo ; Hydrolases ; Enzima ; Rodentia ; Mammalia ; Vertebrata ; Aparato genital macho patología ; Endocrinopatía ;

Localisation / Location

INIST-CNRS, Cote INIST : 19134, 35400005181178.0050