Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl metabolizing enzymes. II. Aromatic aldehydes.
The molecular cytotoxic mechanisms of dietary benzaldehydes towards hepatocytes and its modulation by metabolizing enzymes were compared. Salicylaldehyde was found to be the most cytotoxic followed by cinnamaldehyde and both rapidly depleted some glutathione before an inhibition of respiration occurred, which preceded cell lysis. Reactive oxygen species were formed, but lipid peroxidation was induced with cinnamaldehyde, but not salicylaldehyde. Glutathione depleted hepatocytes were more susceptible to cytotoxicity. Mitochondrial toxicity and cytotoxicity were prevented by glycolytic substrates (e.g. fructose), citric acid cycle substrates (e.g. glutamine) or cyclosporin, the mitochondrial permeability transition inhibitor. Inhibition of mitochondrial ALDH with chloral hydrate, crotonaldehyde or citral or decreasing mitochondrial NAD+ with rotenone increased cinnamaldehyde induced cytotoxicity with a much smaller effect on salicylaldehyde induced cytotoxicity. Cyanamide was the most effective ALDH inhibitor for increasing cinnamaldehyde induced cytotoxicity, presumably because cyanamide also inhibits microsomal ALDH. Although cinnamaldehyde was a better substrate than salicylaldehyde for ADH1, cytosolic NADH generators (e.g. xylitol) prevented salicylaldehyde and cinnamaldehyde cytotoxicity similarly. This could be explained as salicylaldehyde was not a substrate for the ALDHs and would then be more dependent on ADH for detoxification.
Niknahad
Hossein
H
Faculty of Pharmacy, Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, Shiraz, 71345, Fars, Iran.
Shuhendler
Adam
A
Galati
Giuseppe
G
Siraki
Arno G
AG
Easson
Elaine
E
Poon
Raymond
R
O'Brien
Peter J
PJ
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000447:Aldehydes; D000444:Aldehyde Dehydrogenase; D005978:Glutathione