Subchronic Effects Of Smokeless Tobacco Extract On Hepatic Lipid Peroxidation And The Increased Excretion Of Urinary Metabolites

Since the use of tobacco is a chronic process, the effects of an aqueous extract of STE in rats following low-dose exposure were examined. Female Sprague-Dawley rats were treated orally with 25mg STE/kg every other day for 105 days. The effects of subchronic treatment of STE on hepatic microsomal and mitochondrial lipid peroxidation were assessed.37 Urinary excretion of the four lipid metabolites malondialdehyde, formaldehyde, acetaldehyde, and acetone was monitored by HPLC, with maximum increases being observed between 60 and 75 days of treatment. The assessment of lipid peroxidation was based on the formation of thiobarbituric acid-reactive substances (TBARS) over the 105 days of the study.

An age-dependent increase in lipid peroxidation was observed in control animals. Over the 105 days of the study, lipid peroxidation increased by 1.9-fold in hepatic mitochondria and 1.6-fold in hepatic microsomes of control animals. In rats treated subchronically with STE, time-dependent increases in lipid peroxidation associated with hepatic mitochondria and microsomes were observed relative to the control animals. In hepatic mitochondria, a 2.7-fold increase in lipid peroxidation was observed after 45 days of treatment and remained constant thereafter, relative to the control animals. In hepatic microsomes, a time-dependent increase in lipid peroxidation was observed, with the greatest increase (3.3-fold) occurring after 90 days of STE treatment.37

The concurrent detection of lipid metabolites by HPLC provides a rapid, convenient, noninvasive method for assessing oxidative tissue damage and cytotoxicity by foreign chemicals.2937 Urine samples were collected after STE treatment over dry ice for 6.0-h time intervals on the indicated days, and the results are expressed as nmol/kg body weight/6.0h. In control animals, time-dependent increases occurred in the urinary excretion of the four lipid metabolites over the 105 days of the study. Increases of 1.9-, 1.5-, 1.6-, and 1.5-fold occurred in the urinary excretion of MDA, FA, ACT, and ACON, respectively, between days 0 and 105 by control rats. MDA excretion in STE-treated rats was significantly different from control animals by the 10th day of treatment, with a 1.9fold increase occurring by day 30, and a maximum increase of 2.3-fold occurring by day 45. No further increases in MDA urinary excretion occurred thereafter during the remainder of the 105-day study. The urinary excretion of FA in STE-treated rats relative to control animals significantly increased by day 20, with a 1.3-fold increase on day 30 and a maximum increase of 2.0-fold on day 60.

The urinary excretion of FA remained relatively constant thereafter in the STE-treated animals throughout the remainder of the 105-day study as compared with the control rats. The urinary excretion of ACT in STE-treated rats was significantly greater than in control animals by the 10th day of the study, with a maximum increase in ACT of 1.9-fold occurring relative to control animals on day 50 of the study. The excretion of ACT by STE-treated rats remained relatively constant thereafter as compared with the control animals. The urinary excretion of ACON was significantly elevated in the urine of STE-treated animals by the 10th day of the study, relative to the control animals. A maximum increase in the urinary excretion of ACON in STE-treated rats of 1.6-fold occurred by day 50 of the study and remained relatively constant thereafter as compared with the control animals during the remainder of the study. The results clearly demonstrate that a chronic low dose of STE treatment induces oxidative stress, resulting in tissue-damaging effects, which contributes to the toxicity and carcinogenicity of STE.37

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