Effects of cis-diamminedichloroplatinum(II) on rabbit kidney in vivo and on rabbit renal proximal tubule cells in culture.
The nephrotoxic potential of cis-diamminedichloroplatinum(II) (CDDP) in rabbits, as well as its effect on cell viability, cellular synthetic activity, and specific enzyme activities in rabbit renal proximal tubule cells, was investigated. Male New Zealand White rabbits were given a single i.v. dose of either 2.5 or 5.0 mg/kg CDDP via the ear vein and sacrificed 5 days later. No drug-induced changes were observed in the kidneys of rabbits given 2.5 mg/kg CDDP. However, histopathological examination of kidneys from rabbits administered 5.0 mg/kg CDDP revealed marked tubular degeneration and necrosis, with the majority of lesions being situated in the outer zone of the cortex. This is in contrast to the effect of CDDP in the kidney of the rat where the necrosis is reported to be predominantly localized to the pars recta of the proximal tubule in the outer stripe of the medulla. The results from the in vitro experiments indicated that the viability of cells after a 6-h exposure to CDDP at concentrations up to 100 microM was greater than 95%. However, a dose-dependent decrease in cell viability was obtained after 24 h exposure with a TD50 (50% viability) of approximately 90 microM. In addition, the results after 24 h exposure to CDDP also indicated that Na+, K+-ATPase, a basolateral membrane marker enzyme, and alkaline phosphatase, a brush-border marker enzyme, were inhibited by 35-40% and 20%, respectively. No effect on succinic dehydrogenase, a mitochondrial marker enzyme, was obtained. Inhibition of all three marker enzymes was minimal at 6 h posttreatment. On the other hand, inhibition of DNA, RNA, and protein syntheses was evident as early as 6 h posttreatment with DNA (48-77%) and RNA (36-77%) syntheses being inhibited to a greater extent than protein synthesis (14-33%). These results demonstrate that inhibition of renal synthetic activity by CDDP, rather than its effect on enzyme activity, precedes the onset of cell lethality and may therefore be an important event in the initiation of CDDP-induced nephrotoxicity.
Tay
L K
LK
Department of Experimental Toxicology, Bristol-Myers Company, Syracuse, New York 13221.
Bregman
C L
CL
Masters
B A
BA
Williams
P D
PD
D000251:Adenosine Triphosphatases / Q000032:analysis; D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D001806:Blood Urea Nitrogen; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D009696:Nucleic Acids / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011817:Rabbits
D009696:Nucleic Acids; D000469:Alkaline Phosphatase; D000251:Adenosine Triphosphatases; D002945:Cisplatin