Cisplatin nephrotoxicity and protection by silibinin.
BACKGROUND
The anticancer drug cisplatin is know to have toxic side-effects on different segments of the nephron. The flavonoid silibinin has previously been shown to be protective in models of hepatotoxicity. The aim of the present study was to evaluate, whether silibinin can also ameliorate alterations in renal glomerular and tubular function and tubular morphology induced by cisplatin.


METHODS
In a rat model renal damage was induced by a single injection of cisplatin (5 mg/kg body weight). The protective effects of silibinin were studied in rats that received the flavonoid (200 mg/kg body weight, i.v.) 1 h prior to the administration of cisplatin. Kidney function was monitored by analysing urinary markers of glomerular and tubular function over a period of 11 days. Animals of a second group, with identical treatment, were sacrificed 4 days after drug application for an evaluation of tubular morphology at the light-microscopical level.


RESULTS
Administration of cisplatin caused a decline in kidney function within a day following treatment. Symptoms observed were for example decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting. The effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Impairment of proximal tubular function was ameliorated, that is enzymuria and magnesium wasting was less pronounced. Silibinin alone had no effect on kidney function. Treatment with silibinin distinctly diminished morphological alterations observed in the S3-segment of the proximal tubule 4 days after cisplatin administration.


CONCLUSIONS
The effects of cisplatin on glomerular and proximal tubular function as well as proximal tubular morphology could totally or partly be ameliorated by silibinin. It is concluded the silibinin can act as a nephroprotectant and it is suggested that it could have beneficial effects on the kidney in clinical settings.
Gaedeke
J
J
Division of Nephrology, Medical School Hannover, Germany.
Fels
L M
LM
Bokemeyer
C
C
Mengs
U
U
Stolte
H
H
Lentzen
H
H
D000118:Acetylglucosaminidase / Q000652:urine; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D001835:Body Weight; D018826:CD13 Antigens / Q000652:urine; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000652:urine; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008274:Magnesium / Q000652:urine; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012838:Silymarin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005353:Fibronectins; D012838:Silymarin; D003404:Creatinine; D000118:Acetylglucosaminidase; D018826:CD13 Antigens; D008274:Magnesium; D002945:Cisplatin