Hepatotoxicity and Nephrotoxicity Produced by 4-Hydroxy-2-Nonenal (4-HNE) Following 4-Week Oral Administration to Sprague-Dawley Rats

Abstract

4-Hydroxy-2-nonenal (4-HNE) is a major end product of lipid peroxidation of membrane n-6 polyunsaturated fatty acids, which are found in food products. In order to examine the toxicity attributed to 4-HNE, a subacute toxicity study was conducted in Sprague-Dawley (SD) rats. For this study, 4 groups of 10 male and 10 female rats were administered by gavage either 0 (control), 0.5, 2.5, or 12.5 mg 4-HNE/kg body weight/d for 28 d, and then sacrificed for blood and tissue sampling. No significant changes in body weight or clinical signs were observed, but biochemical analysis showed significant alterations in hepatotoxicity biomarkers, such as levels of serum albumin and total bilirubin, and aspartate aminotransferase (AST) activity, and in nephrotoxicity biomarkers, such as levels of blood urea nitrogen (BUN) and creatinine and activity of alkaline phosphatase (ALP), and urinary creatinine and protein levels at 0.5 mg/kg/d. In addition, significant increases in kidney and brain weights and a significant decrease in small intestine weight were noted at 12.5 mg/kg/d. Histologic examinations of kidneys showed hyaline droplets or accumulation of hyaline bodies in renal tubules and degeneration of tubular epithelium cells. These results demonstrate that oral daily exposure to 4-HNE for 28 d produced hepatotoxicity and nephrotoxicity. The no-observed-adverse-effect level (NOAEL) for 4-HNE was calculated to be <0.5 mg 4-HNE/kg/d.

Acknowledgments

This research was supported by the Korean Food & Drug Administration in 2009 (grant 09162KFDA541).