Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis.
BACKGROUND
Reactive oxygen metabolites (ROM) are important mediators of cisplatin-induced nephrotoxicity and apoptosis. The site and source of generation of these metabolites are not well defined. Cytochrome P450 (CYP) are heme-containing enzymes that can generate ROM during the oxidative metabolism of exogenous and endogenous compounds. CYP2E1 was identified and localized to the kidney proximal tubule. There is evidence to suggest that CYP2E1 is involved in the generation of ROM.


METHODS
The current study was performed utilizing CYP2e1 null mice (CYP2e1-/-). Cisplatin nephrotoxicity was induced in mice by single intraperitoneal injection of cisplatin and animals were sacrificed 72 hours later. Renal function was assessed and various biochemical tests were performed, including histologic studies.


RESULTS
CYP2e1-/- demonstrated marked functional and histologic protection against cisplatin-induced renal injury. Incubation of CYP2e1-/- kidney slices with cisplatin resulted in significant decrease in the generation of ROM and attenuation of cytotoxicity as compared to that of wild-type mice (CYP2e1+/+). Cisplatin-induced apoptosis was also markedly reduced in the CYP2e1-/- mice. Direct incubation of cisplatin with the microsomes isolated from CYP2e1-/- kidney cortex produced significant decrease in the generation of hydrogen peroxide, catalytic iron content, and hydroxyl radical formation compared to CYP2e1+/+ microsomes.


CONCLUSIONS
Our results thus demonstrate a pivotal role of CYP2E1 in cisplatin-induced nephrotoxicity and apoptosis. We postulate that the interaction of cisplatin with CYP2E1 results in the generation of ROM that causes renal injury and initiates apoptosis.
Liu
Hua
H
Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Baliga
Radhakrishna
R
D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis; D002945:Cisplatin; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D019392:Cytochrome P-450 CYP2E1; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D002945:Cisplatin