The acrolein cytotoxicity and cytoprotective action of α-tocopherol

Abstract

The influence of acrolein on hepatocytes and the effect of alpha-tocopherol on acrolein cytotoxicity were investigated using primary cultured rat hepatocytes. Hepatocellular injury was dependent on both acrolein concentration in medium and on duration of exposure. Treatment of hepatocytes with 100 microM acrolein resulted in a marked loss of cellular glutathione (GSH) within 15 min, gradual accumulation of cellular lipid peroxide (LPO) and subsequent lactate dehydrogenase (LDH) leakage in the medium from 3 hr after exposure to acrolein. Cellular GSH peroxidase (GSH-Px) activity at 2 hr was significantly decreased. Electron microscopic examination on hepatocytes at 8 hr revealed a marked swelling of mitochondria and ruptures of the plasma membrane. Simultaneous treatment with 100 microM acrolein and 20 microM alpha-tocopherol did not prevent the loss of cellular GSH, though it prevented the LPO accumulation and the LDH leakage. The decrease of cellular GSH-Px activity with acrolein treatment was not mitigated by co-treatment with alpha-tocopherol. Ultrastructural alterations of hepatocytes induced by acrolein were minimized by co-treatment with alpha-tocopherol. In conclusion, acute loss of GSH and GSH-Px may increase cellular LPO and lead to hepatocellular injury, though suppression of cellular LPO accumulation by alpha-tocopherol can prevent the hepatocellular injury, even under condition of lack of GSH and GSH-Px.

Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity

“…These processes include apoptotic stress (caused by inhibition of nuclear factor kappa beta function in hepatocytes) and ER stress (as demonstrated in tunicamycin‐treated hepatocytes) . Other groups have shown that VitE inhibits hepatotoxicity . Ballooned hepatocytes, a hallmark of lipotoxicity in NASH, have been shown to exhibit apoptotic and ER stress .…”

“…14 Other groups have shown that VitE inhibits hepatotoxicity. [33][34][35][36] Ballooned hepatocytes, a hallmark of lipotoxicity in NASH, have been shown to exhibit apoptotic and ER stress. 12,37 NASH CRN data in humans with NASH enrolled in PIVENS demonstrated that VitE significantly reduced hepatocyte ballooning and serum ALT (a surrogate marker of hepatocyte injury).…”

Cytotoxicity of β-carotene cleavage products and its prevention by antioxidants.

“…Trolox -representing a water-soluble vitamin E derivative, 6-hydroxy-2,5,7,8-tetramethylchromane-2-carbonic acid -inhibits peroxynitrite-mediated oxidative stress (Salgo & Pryor, 1996), activates pregnane-X-receptor which regulates genes involved in xenobiotic detoxification (Traber, 2004), can protect from aldehyde toxicity (Watanabe et al, 1992), and has been demonstrated to inhibit apoptosis and to reduce cytotoxicity in various cell types, such as thymocytes and lymphocytes (Wu et al, 1990;McClain et al, 1995). Similarly, ascorbic acid has been demonstrated to inhibit peroxynitrite-induced apoptosis (Sandoval et al, 1997), to promote detoxification and elimination of 4-hydroxy-2(E)-nonenal (Miranda et al, 2009) and, together with N-acetylcystein, to protect against aldehyde toxicity (Sprince et al, 1975).…”