Effects of 1-Morpholinoacetyl-2-Methyl-3-Phenyl-4-Oxo-1,2, 3, 4-Tetrahydro Quinazoline Hydrochloride (Hq-275) on ?-Naphtyl Isothiocyanate- And/or Thioacetamide-Induced Liver Damage in Rats

Abstract

Abstract-Pharmacological properties of 1-morpholinoacetyl-2-methyl-3-phenyl-4 oxo-1, 2, 3, 4-tetrahydro quinazoline hydrochloride (HQ-275), which has a potent choleretic activity, on ANIT and TAA-hepatic injury have been investigated in rats for biochemical, histochemical levels and the functions in the liver. Regarding the actions of biliary and solid content excretion, HQ-275 demonstrates differences bet ween normal rats and the groups administered ANIT and/or TAA, and also the low ered values of Al-P, transaminases and bilirubin in plasma, elevated by the ANIT poisoning. Thus a comparable effect of HQ-275 against TAA-poisoning was not observed. TAA-induced elevation of the plasma-lipid level was significantly pre vented by the administration of HQ-275. Moreover, under light microscopical ex amination, the decrease of 5'-N by the ANIT-poisoning was prevented even with small doses of HQ-275 3-6 mg/kg, p.o. Elevation of the cholesterol level in plasma and decrease of ATP-ase in histochemical findings by ANIT-intoxication were not in themselves recognizable.Changes of Na+ and K+ in bile and water content of liver by poisoning of ANIT were clearly prevented with HQ-275. On the other hand, HQ-275 revealed no effects on the actions produced by TAA-intoxication except for those mentioned.Such being the case it can be concluded that HQ-275 inhibits the ANIT-induced hepatic injury to a greater extent than the TAA-induced hepatic damage for biochemical and histochemical levels.In a previous report from our laboratory, l-morpholinoacetyl-2-methyl-3-phenyl-4 oxo-1, 2, 3, 4-tetrahydroquinazoline hydrochloride (HQ-275) was demonstrated to have a potent inhibitory effect against experimental hepatic injury produced by carbon tetra chloride (CC14) in rats with respect to both histological findings and transaminase levels (1-4). It is also well known that cc-Naphtyl Isothiocyanate (ANIT) and Thioacetamide (TAA) are also agents which produce experimental liver damage in laboratory animals in addition to CC14 and ethionine. For example, a single dose of ANIT results in eleva tion of transaminases (s-GOT and s-GPT), alkali phophatase (Al-P), cholesterol and bili rubin in blood and declines of ATP-ase and 5'-nucleotidase (5'-N) activities in liver cells , respectively. Furthermore, in respect to bilirubin, rats treated with ANIT produced a hepatic bile stagnation, that is obstructive icterus, due to occlusion of the common bile duct by calculus and/or cancer of the pancreas and a mild centrilobular necrosis border ing ballooning. On the other hand, hepatic changes by TAA , which result in a similar lesion can be produced by feeding thiourea, are histologically sinusoidal congestion , hy dropic swelling and increased mitosis (5, 6). Moreover , decrease of hepatic protein, lipids esterase activity, and increase in hepatic water content and Al-P activity developments are recognized histochemically (7). But, in serum, Al-P activity is increased and esterase activity is reduced (8,9). Therefore, as indices of the drugs against TAA-into...