• The Korean Journal of Pharmacology
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• v.32 no.3
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• pp.407-416
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• 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 Chest Surgery
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• v.33 no.7
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• pp.531-540
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• 2000

Baclgrpimd; Recent studies have suggested that the cardioprotective effect of ischemic preconditioning(IP) is closely related to glycogen depletion and attenuation of intracellular acidosis. In the present study, the authors tested this hypothesis by perfusion isolated rabbit hearts with glucose(G) is closely related to glycogen depletion and attenuation of intracellular acidosis. In the present study, the authors tested this hypothesis by perfusion isolated rabbit hearts with glucose(G)-free perfusate. Material and Method; Hearts isolated from New Zealand white rabbits(1.5~2.0 kg body weight) were perfused with Tyrode solution by Langendorff technique. After stabilization of baseline hemodynamics, the hearts were subjected to 45 min global ischemia followed by 120 min reperfusion with IP(IP group, n=13) or without IP(ischemic control group, n=10). IP was induced by single episode of 5 min global ischemia and 10 min reperfusion. In the G-free preconditioned group(n=12), G depletion was induced by perfusionwith G-free Tyrode solution for 5 min and then perfused with G-containing Tyrode solution for 10 min; and 45 min ischemia and 120 min reperfusion. Left ventricular functionincluding developed pressure(LVDP), dP/dt, heart rate, left ventricular end-distolic pressure(LVEDP) and coronary flow (CF) were measured. Myocardial cytosolic and membrane PKC activities were measured by 32P-${\gamma}$-ATP incorporation into PKC-specific peptide and PKC isozymes were analyzed by Western blot with monoclonal antibodies. Infarct size was determined by staining with TTC(tetrazolium salt) and planimetry. Data were analyzed by one-way analysis of variance (ANOVA) and Turkey's post-hoc test. Result ; In comparison with the ischemic control group, IP significantly enhanced functional recovery of the left ventricle; in contrast, functional significantly enhanced functional recovery of the left ventricle; in contrast, functional recovery were not significantly different between the G-free preconditioned and the ischemic control groups. However, the infarct size was significantly reduced by IP or G-free preconditioning(39$\pm$2.7% in the ischemic control, 19$\pm$1.2% in the IP, and 15$\pm$3.9% in the G-free preconditioned, p<0.05). Membrane PKC activities were increased significantly after IP (119%), IP and 45 min ischemia(145%), G-free [recpmdotopmomg (150%), and G-free preconditioning and 45 min ischemia(127%); expression of membrane PKC isozymes, $\alpha$ and $\varepsilon$, tended to be increased after IP or G-free preconditioning. Conclusion; These results suggest that in isolated Langendorff-perfused rabbit heart model, G-free preconditioning (induced by single episode of 5 min G depletion and 10 min repletion) colud not improve post-ischemic contractile dysfunction(after 45-minute global ischemia); however, it has an infarct size-limiting effect.