Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl-metabolizing enzymes. I. Aliphatic alkenals.
The cytotoxicity of alkenals towards hepatocytes was related to their electrophilicity not their hydrophobicity as cytotoxicity decreased as the chain length increased from acrolein to hexenal and then cytotoxicity increased from hexenal to nonenal. The sequence of events found was rapid glutathione depletion, lipid peroxidation, and inhibition of respiration before cell lysis occurred. Cytotoxicity markedly increased if glutathione was depleted beforehand. Although acrolein-induced cytotoxicity was only delayed by antioxidants or glycolytic substrates (e.g. fructose), it was prevented by NADH generators (e.g. xylitol and sorbitol) due to increased metabolism by ADH1. Cytotoxicity induced by trans,trans-2,4-decadienal (decadienal), on the other hand, was prevented by antioxidants and/or glycolytic substrates but was not prevented by NADH generators. Decadienal-induced cytotoxicity was also more increased by mitochondrial ALDH2 inhibitors than acrolein and was more increased by decreasing mitochondrial NAD+ with rotenone or decreased by increasing mitochondrial NAD+ with oxaloacetate. This suggests that the high electrophilicity of acrolein makes acrolein a more promiscuous inhibitor than decadienal. This results in the inactivation of more enzymes required for cell viability including the cytosolic and mitochondrial ALDHs as well as other enzymes (e.g. mitochondrial) making the reductive detoxication of acrolein by ADH1 more important than the oxidative detoxification by ALDHs. Decadienal is detoxified by all cytosolic and mitochondrial ALDHs and is less dependent on ADH1 for detoxication. There was also marked cytotoxic synergism between acrolein and decadienal presumably because of ALDH inactivation by acrolein.
Niknahad
Hossein
H
Faculty of Pharmacy, Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, 71345, Fars, Shiraz, Iran.
Siraki
Arno G
AG
Shuhendler
Adam
A
Khan
Sumsullah
S
Teng
Shirley
S
Galati
Giuseppe
G
Easson
Elaine
E
Poon
Raymond
R
O'Brien
Peter J
PJ
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000447:Aldehydes; D000444:Aldehyde Dehydrogenase