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 last and significantly higher plasma clearance and volume of distribution (Vss) following intravenous administration of 14C-testosterone. Reductions in plasma testosterone levels were observed in lansoprazole-treated animals but no significant changes in plasma LH or FSH levels were detected. Lansoprazole-treated animals exhibited lower plasma prolactin and intratesticular testosterone concentrations, which might play a role in LCT development. No marked effects on testicular CYP-dependent testosterone metabolism were observed. In conclusion, these findings are consistent with the hypothesis that hepatic CYP induction contributes to the reduction in circulating testosterone levels in lansoprazole-treated animals, which might play a role in LCT development.