Functional modulation of the mineralocorticoid receptor by cis-diamminedichloroplatinum (II).
BACKGROUND
Renal salt wasting and hypotension are some of the frequent complications in patients treated with cis-diamminedichloroplatinum (II) (cDDP), and it is suggested that cDDP produces an abnormality in the renin-angiotensin system. However, not only the underlying mechanism but also prophylactic treatment of this cDDP toxicity remains unknown. In the present study, we investigated the molecular mechanism of this cDDP-induced disturbance of renal sodium handling with focusing on the effect of cDDP on mineralocorticoid receptor (MR) function.


METHODS
The effect of cDDP was studied on nuclear translocation, DNA binding activity, and transactivation function of the MR.


RESULTS
In a transient transfection assay, cDDP suppressed MR-dependent reporter gene expression. This cDDP-mediated repression of MR function, at least in part, is suggested to be due to the generation of reactive oxygen species and a subsequent decrease in ligand-dependent nuclear translocation and suppression of the interaction with DNA of the MR. This redox-dependent repression of MR function both in vitro and in vivo was reversed by treatment with reducing reagents. Moreover, cDDP, most possibly via formation of DNA adducts, inhibited MR-DNA interaction in a redox-independent fashion.


CONCLUSIONS
MR function is impaired by cDDP at multiple levels, via redox-dependent and -independent mechanisms.
Iida
T
T
Second Department of Internal Medicine, Asahikawa Medical College, Midorigaoka, Asahikawa, Japan.
Makino
Y
Y
Okamoto
K
K
Yoshikawa
N
N
Makino
I
I
Nakamura
T
T
Tanaka
H
H
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D012964:Sodium; D002945:Cisplatin