Paper Information

Title: 

CYTOTOXIC MECHANISM AND METABOLISM OF AROMATIC ALDEHYDES IN ISOLATED RAT HEPATOCYTES

Type: SPEECH
Author(s): NIKNAHAD H.*
 
 *DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY, FACULTY OF PHARMACY, SHIRAZ UNIVERSITY OF MEDICAL SCIENCES, SHIRAZ, FARS, IRAN, 71345
 
Name of Seminar: IRANIAN CONGRESS OF TOXICOLOGY
Type of Seminar:  CONGRESS
Sponsor:  SOCIETY OF TOXICOLOGY
Date:  2004Volume 8
 
 
Abstract: 

Dietary benzaldehydes such as cinnamaldehyde (CA) and salicylaldehyde (SA) are present in cinnamon and vanilla as well as in the essential oils of the seeds and kernels of bitter almonds, apricots, peaches, plums and cherries. They are also ingested as food additives, preservatives or flavoring agents. Therefore, their molecular cytotoxic mechanisms and metabolism by modulation of metabolizing enzymes were studied in isolated rat hepatocytes. SA was found to be the most cytotoxic followed by CA. Other benzaldehyde was less toxic. They rapidly depleted GSH before inhibiting mitochondrial respiration, which preceded cell lysis. Reactive oxygen species were formed but lipid peroxidation was induced by CA but not SA. GSH depleted hepatocytes were more susceptible to these copounds. Cytotoxicity was prevented by glycolytic substrates, citric acid cycle substrates or cyclosporin, a mitochondrial permeability transition inhibitor. Inhibition of mitochondrial ALDH with chloral hydrate, crotonaldehyde, or citral increased CA cytotoxicity with a much smaller effect of SA cytotoxicity. Cyanamide was the most effective ALDH inhibitor for increasing CA but not SA cytotoxicity possibly because it also inhibits microsomal ALDH.
 Increasing hepatocyte NADH levels with sorbitol or xylitol prevented CA- and SA-induced cytotoxicity, but not if alcohol dehydrogenase was inhibited with methyl pyrazole. Decreasing mitochondrial NAD+ with rotenone markedly increased CA but not SA toxicity. Thgerefore, it seems that CA was a good substrate for both mitochondrial and microsomal aldehyde dehydrogenases. The marked increase in CA toxicity by rotenone suggests that ALDH2 plays an important role in detoxifying CA. Alcohol dehydrogenase was also clearly important in detoxification of SA and CA, as cytotoxicity was prevented by NADH generators, but not if alcohol dehydrogenase was inhibited with methyl pyrazole.
The results suggest that unmetabolized SA and CA could bind to critical intracellular targets, e.g. proteins, especially in mitochondria, resulting in cytotoxicity.

 
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