title: Cisplatin inhibits testosterone synthesis by a mechanism that includes the action of reactive oxygen species (ROS) at the level of P450scc.
abstract: Cisplatin (Cs) is a chemotherapeutic agent able to generate reactive oxygen species (ROS) which are linked to several side effects of the drug. Even when it is known that Cs produces Leydig cell dysfunction, it is unknown whether this particular side effect is mediated by ROS. The aim of this study was to evaluate the in vitro effects of Cs on testosterone production and the participation of ROS in this effect. We demonstrate that Cs promotes the generation of ROS in a time-, and concentration-dependent fashion, not only in mouse testicular interstitial cells but also in MA-10 Leydig cells. Also, Cs inhibits testosterone synthesis in a concentration-dependent fashion (5-50 μM for 4 h) and to a similar extent, in cells exposed to human chorionic gondadotropin hormone (hCG), to an analog of the second messenger cAMP (8Br-cAMP) or to a freely diffusible cholesterol analog (22R-hydroxycholesterol). However, this treatment does not inhibit the conversion of pregnenolone to testosterone. These data suggest that Cs exerts its inhibitory action on testosterone synthesis by an action at the level of P450scc. We also demonstrated that an antioxidant impairs the inhibitory effect of Cs on the conversion of the cholesterol analog into pregnenolone and that Cs does not change the expression level of P450scc mRNA. Therefore, it is concluded that Cs inhibits testosterone synthesis by a mechanism that includes the inhibition of P450scc by ROS.
authors.affiliation: Institute of Biomedical Investigations (INBIOMED), Department of Biochemistry, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Mercedes Mori Sequeiros
authors.initials: MM
authors.lastname: García
authors.forename: Andrea
authors.initials: A
authors.lastname: Acquier
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Suarez
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Gomez
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gorostizaga
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Mendez
authors.forename: Cristina
authors.initials: C
authors.lastname: Paz
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001483:Base Sequence; D002460:Cell Line; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors* / Q000235:genetics; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D066298:In Vitro Techniques; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011284:Pregnenolone / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D006063:Chorionic Gonadotropin; D006888:Hydroxycholesterols; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C003585:22-hydroxycholesterol; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013739:Testosterone; D011284:Pregnenolone; D002786:Cholesterol Side-Chain Cleavage Enzyme; D002945:Cisplatin