• The Korean Journal of Pharmacology
• /
• v.32 no.3
• /
• pp.407-416
• /
• 1996

The reactive intermediates formed during the metabolism of therapeutic agents, toxicants and carcinogens by cytochromes P450 are frequently capable of covalently binding to tissue macromolecules and causing tissue damage. It has been shown that YH439, a congener of malotilate, is effective in suppressing hepatic P450 2E1 expression. The present study was designed to further establish the mechanistic basis of YH439 protection against toxicant by assessing its effects against chemical-mediated potentiated hepatotoxicity. Retinoyl palmitate (Vit-A) pretreatment of rats for 7 days substantially enhanced carbon tetrachloride hepatotoxicity, as supported by an ${\sim}5-fold$ increase in serum alanine aminotransferase (ALT) activity, as compared to $CCl_4$ treatment alone. The elevation of ALT activity due to Vit-A was completely blocked by the treatment of $GdCl_3$ a selective inhibitor of Kupffer cell activity. Concomitant pretreatment of rats with both YH439 and Vit-A resulted in a 94% decrease in Vit-A-potentiated $CCl_4$ hepatotoxicity. YH439 was also effective against propyl sulfide-potentiated $CCl_4-induced$ hepatotoxicity. Whereas propyl sulfide (50 mg/kg, 7d) enhanced $CCl_4-induced$ hepatotoxicity by >5-fold, relative to $CCl_4$ treatment alone, concomitant treatment of animals with both propyl sulfide and YH439 at the doses of 100 and 200 mg/kg prevented propyl sulfide-potentiated $CCl_4$ hepatotoxicity by 35% and 90%, respectively. Allyl sulfide, a suppressant of hepatic P450 2E1 expression, completely blocked the propyl sulfide-enhanced hepatotoxicity, indicating that propyl sulfide potentiation of $CCl_4$ hepatotoxicity was highly associated with the expression of P450 2E1 and that YH439 blocked the propyl sulfide-enhanced hepatotoxicity through modulation of P450 2E1 levels. Propyl sulfide- and $CCl_4-induced$ stimulation of lipid peroxidation was also suppressed by YH439 in a dose-related manner, as supported by decreases in malonedialdehyde production. The role of P450 2E1 induction in the potentiation of $CCl_4$ toxicity and the effects of YH439 were further evaluated using pyridine as a P450 2E1 inducer. Pyridine pretreatment substantially enhanced the $CCl_4$ hepatotoicity by 23-fold, relative to $CCl_4$ alone. YH439, however, failed to reduce the pyridine-potentiated toxicity, suggesting that the other form(s) of cytochroms P450 inducible by pyridine, but not suppressible by YH439 treatment, may play a role in potentiating $CCl_4-induced$ hepatotoxicity. YH439 was capable of blocking cadmium chloride-induced liver toxicity in mice. These results demonstrated that YH439 efficiently blocks Vit-A-enhanced hepatotoxiciy through Kupffer cell inactivation and that the suppression of P450 2E1 expression by YH439 is highly associated with blocking of propyl sulfide-mediated hepatotoxicity.

• Journal of Food Hygiene and Safety
• /
• v.26 no.2
• /
• pp.107-113
• /
• 2011

Plantago asiatica L. (PA), which is widely distributed in Korea, Japan and China, has traditionally been used as a popular folk medicine for the treatment of liver diseases. A variety of activities of PA was reported, that is hepatoprotective, anti-inflammatory, anti-glycation and anti-oxidant effect. Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent and has been reported to induce renal proximal tubular necrosis. In the present study, pre-treatment with PA extract (PAE) in Wistar rat followed by Fe-NTA i.p. treatment (13.5 mg Fe/kg body weight) was performed to detect the renal protective effect of PAE. Only Fe-NTA treated group showed increases in the level of serum blood urea nitrogen (BUN) and serum creatinine (Cr), and renal tissue malondialdehyde (MDA), product of lipid peroxidation. Moreover, the level of biomarkers indicate the antioxidants status, reduced glutathione (GSH), glutathione-S-transferase (GST) and glutathione reductase (GR) were decreased. However, PAE pre-treated group showed decreases in the levels of serum BUN, serum Cr and renal tissue MDA in concentration dependent manner and increases in the level of GSH, GST and GR. These results are significantly different (p < 0.05) to the other groups. Our data suggest that PAE may be used as an chemopreventive material against Fe-NTA-mediated renal oxidative stress.