Effect of cytochrome P450 2E1 inhibitors on cisplatin-induced cytotoxicity to renal proximal tubular epithelial cells.
BACKGROUND
We have demonstrated an important role of cytochrome P450 (CYP) as a significant source of catalytic iron in reactive oxygen species (ROS)-mediated cisplatin (CP)-induced renal injury.


METHODS
The current study was designed to explore the role of CYP2E1 as a site for ROS generation and a source of iron in CP-induced cytotoxicity to the LLC-PK1 cells.


RESULTS
CYP2E1 was identified in the LLC-PK1 cells. Exposure of LLC-PK1 cells to CP resulted in marked generation of hydrogen peroxide (H2O2), reduction of CYP2E1 content, increase in catalytic iron and hydroxyl radical formation accompanied by significant cytotoxicity. CYP2E1 inhibitors markedly reduced H2O2 generation with the preservation of CYP2E1 content, markedly decreased in iron and hydroxyl radical formation associated with significant attenuation in cytotoxicity.


CONCLUSIONS
CYP2E1 plays an important role in CP-induced cytotoxicity by severing as a site for the generation of ROS and a significant source of catalytic iron.
Liu
Hua
H
Department of Pediatrics, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Baliga
Mithra
M
Baliga
Radhakrishna
R
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D006861:Hydrogen Peroxide / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine
D000970:Antineoplastic Agents; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019392:Cytochrome P-450 CYP2E1; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D002945:Cisplatin