Induction of Leydig cell tumors by lacidipine via up-regulation of the LHRH receptor on Leydig cells in rats.
Long-term (78 weeks) administration of lacidipine, a dihydropyridine calcium antagonist, increased the incidence of Leydig cell tumors (LCTs) in Sprague-Dawley rats. Lacidipine also increased and decreased the plasma luteinizing hormone (LH) and testosterone levels, respectively. Leydig cells from lacidipine-treated rats showed increases in luteinizing hormone-releasing hormone (LHRH) receptor expression, protein kinase C (PKC) activity, expression of proto-oncogenes, and 5-bromodeoxyridine uptake; whereas their calcium level, LH receptors, and testosterone content decreased. These data suggest that LHRH receptors play an important role in the development of rat LCTs induced by lacidipine, which activates a cascade of cell cycle-regulatory genes via PKC. When isolated Leydig cells were cultured with lacidipine or nicardipine, these changes in rat Leydig cells were not demonstrable in mice and monkeys, species having many fewer testicular LHRH receptors than rats. Thus, lacidipine may pharmacologically induce LCTs in rats but not in mice, with the difference depending on the presence or absence of testicular LHRH receptors. The induction of LCTs by lacidipine in rats is unlikely to occur in humans, since their Leydig cells lack LHRH receptors.
Hamada
Y
Y
Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Futamura
Y
Y
D000284:Administration, Oral; D000818:Animals; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology* / Q000633:toxicity; D007984:Leydig Cell Tumor / Q000139:chemically induced*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009529:Nicardipine / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011519:Proto-Oncogenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000378:metabolism*; D013045:Species Specificity; D013739:Testosterone / Q000097:blood; D015854:Up-Regulation / Q000502:physiology*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011966:Receptors, LHRH; C060285:lacidipine; D013739:Testosterone; D007986:Luteinizing Hormone; D009529:Nicardipine; D011494:Protein Kinases; D001973:Bromodeoxyuridine