Hypoxia and CCI4-induced liver injury, but not acidosis, impair metabolism of cysteinyl leukotrienes in perfused rat liver

Abstract

Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single-pass perfused rat liver. Hypoxia did not impair uptake of infused [3H]leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent omega-oxidation with subsequent elimination of the omega-oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H]leukotriene E4 addition because of an almost complete absence of omega-oxidation products in bile, whereas N-acetyl-leukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single-pass uptake of [3H]leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H]leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotrienes. Thus, in leukotriene-induced shock syndromes, leukotriene elimination and inactivation may be impaired giving rise to a "vicious circle."

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

“…Using a different HPLC system, the polar fraction separated into different metabolites co-eluting with standards of w-oxidation products of N-acetyl-LTE4 [22]. Less than 3% of the radioactivity taken up was excreted into bile as N-acetyl-LTE,, whereas LTE4 was not detectable in bile.…”

“…In a mutant rat strain with a hereditary defect in biliary excretion of conjugated bilirubin and dibromosulfophthalein, elimination of cysteinyl leukotrienes was also impaired, whereas taurocholate excretion was normal [15-171. Understanding of hepatic leukotriene processing is of importance in view of the previous observations that impairment of hepatic leukotriene elimination may be a major pathophysiological mechanism in diseases like endotoxin shock [18,191, the hepatorenal syndrome [20] and ethanolinduced hepatitis [21]. Hepatic leukotriene processing is also impaired under conditions leading to liver hypoxia and liver cell necrosis [22]. In addition, inhibition of sinusoidal uptake or biliary excretion of cysteinyl leukotrienes may be responsible for side-effects of drugs like cyclosporin [23].…”

Multiple Alterations of Canalicular Membrane Transport Activities in Rats with CCl4-induced Hepatic Injury

“…Experimental hepatic injury (EHI) induced by a single administration of carbon tetrachloride (CCl 4 ) has been widely used as a pathological model for liver diseases, since it is known that CCl 4 produces acute hepatocellular injury with centrilobular necrosis and steatosis (Recknagel, 1967). The effects of CCl 4 -EHI on biochemical characteristics such as increased lipid peroxidation (Recknagel, 1967) and the activities (Mourelle et al, 1987;Romero et al, 1994) of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) and hepatobiliary excretion of xenobiotics (for example, sulfobromophthalein and leukotriene; Iga et al, 1977;Wettstern et al, 1990) have been widely studied. Our earlier study revealed that transport systems for some organic cations on the sinusoidal membrane are prone to damage as the result of CCl 4 -EHI, as demonstrated by a decrease in the in vitro maximal rates of hepatic uptake and efflux without any influence on in vivo canalicular excretion clearance (Hong et al, 2000).…”

Antioxidant Properties of Selected African Vegetables, Fruits and Mushrooms: A Review

“…No evident increase or decrease in the level of ALP was observed. Absence of any concomitant increase of decrease on the ALP levels, under experimental conditions, was attributed to the fact that the single dose, intraperitioneal injection of the carbon tetrachloride at the pre-stated concentration/dosage, may not have caused any significant (P<0.05) billiary tract obstruction or disease [158] while causing acute hepatocellular injury [159]. Also the protective role of Gongronema latifolium in acetaminophen induced hepatic toxicity in Wistar rats was elucidated by [160].…”