The Role of a Liver-Testis Axis in the Development of Leydig Cell Hyperplasia and Tumours
Abstract
Leydig cell hyperplasia and adenomas are frequently observed during chronic carcinogenicity studies with new therapeutic agents, however, the significance of this effect to humans is unknown. Many compounds that produce Leydig cell tumours also induce hepatic cytochromes P450 (CYP) but it is unknown whether these two phenomena are causally related. The aim of this project was to investigate the existence of a liver-testis axis wherein microsomal enzyme inducers enhance testosterone metabolic clearance, resulting in a drop in circulating hormone levels and a consequent hypertrophic response from the hypothalamic-pituitary axis. Lansoprazole was selected as the model compound as it induces hepatic CYPs and produces LCTs in rats (Atkinson et al. , 1990; Masubuchi et al. , 1997a). Effects of lansoprazole treatment (150 mg/kg/day for 14 days) on the liver, testis and endocrine control of the testis in male rats were investigated. The effects of lansoprazole were compared to model CYP inducers (B-NF, PB, PCN and ciprofibrate), the latter not being associated with LCTs. Lansoprazole produced effects on the liver consistent with an increased metabolic capacity, including an increase in total microsomal CYP content, CYP induction (CYP1A1, CYP1A2, CYP2B1, CYP3A and CYP4A1) and enhanced CYP-dependent testosterone metabolism in vitro (i. e. 6β, 7α-, 16α-, 16β-, 2α- and 2β-OHT and androstenedione formation). Furthermore, lansoprazole-treated rats exhibited a significantly smaller AUC…
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