Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status.
ABSTRACT Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin. Blood plasma samples taken at 24 h post-dosing and urine samples collected from 24-31 h post-dosing were analysed by (1)H NMR spectroscopy. Both hypercreatinaemia and hypercreatinuria were found in rats dosed with allyl formate (75 mg/kg), chlorpromazine (30 and 60 mg/kg), alpha-naphthylisothiocyanate (ANIT, 100 mg/kg) and thioacetamide (200 mg/kg), whilst significant hypercreatinuria, but not hypercreatinaemia, was found after dosing with thioacetamide (50 mg/kg). Neither hypercreatinaemia nor hypercreatinuria were found after dosing with allyl formate (25 mg/kg), ethionine (300 and 1000 mg/kg) or ANIT (30 mg/kg). Reduced feeding is known to cause hypercreatinuria in rats and, of the four hepatotoxins that induced hypercreatinaemia and hypercreatinuria at the given time-points, two, chlorpromazine and ANIT, also affected nutritional status with ketosis being clearly identifiable from the plasma (1)H NMR spectra. Thus, the creatine changes induced by ANIT and chlorpromazine are potentially attributable, in whole or in part, to reduced feeding rather than to liver effects alone and, consequently, the results were examined with and without inclusion of the ANIT and chlorpromazine data. With all of the data included, there were eight out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma alanine aminotransferase (ALT) activity. At the same time there were nine out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma aspartate aminotransferase (AST) activity. However, with the ANIT and chlorpromazine data excluded there was complete (six out of six points) correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma AST and ALT in the remaining data. Likewise, with all of the data included, there was some apparent correlation (correlation coefficient, r=0.80) between the group mean levels of plasma AST and plasma creatine when expressed relative to the mean values for controls sampled at the same time-point. However, with the ANIT and chlorpromazine data excluded, that correlation coefficient was increased to 0.95. The findings of these studies suggest that the ANIT- and chlorpromazine-induced creatine changes may have been caused by reduced feeding rather than by liver toxicity. The allyl formate and thioacetamide data indicate that hepatocellular necrosis is accompanied by increases in plasma and urinary creatine, and suggest the possibility of a quantitative relationship between the increases in plasma AST and the increases in plasma creatine that are associated with hepatocellular necrosis. The ethionine and ANIT data suggest that fatty liver (steatosis) and cholestatic damage may not be associated with hypercreatinaemia and hypercreatinuria.
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ABSTRACT: The effect of various hepatotoxicants on urinary taurine and urinary creatine has been studied in the rat. Several hepatotoxic agents, carbon tetrachloride, thioacetamide, galactosamine and allyl alcohol which all caused hepatic necrosis (sometimes accompanied by steatosis), resulted in a rise in urinary taurine and in some cases creatine, when administered to rats. Ethionine and hydrazine also raised urinary taurine but caused only steatosis and did not raise urinary creatine. Therefore urinary taurine and possibly creatine may be useful markers of liver injury and dysfunction. Liver taurine levels were also affected by some of the hepatotoxicants but in those cases where there was a rise in urinary taurine this could not be accounted for by the loss in liver taurine. It is suggested that the increase in urinary taurine is partly due to changes in protein synthesis and hence in sulphur amino acid metabolism caused by hepatotoxic agents. However, bromobenzene did not increase urinary taurine and alpha-naphthylisothiocyanate and lithocholate caused reduced levels. It is suggested that this lack of increase in urinary taurine may be due to depletion of glutathione or interference with the biliary system.Archive für Toxikologie 02/1993; 67(4):244-54. · 5.22 Impact Factor
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ABSTRACT: A single dose of cadmium chloride (3.23 mol Cd2+/kg) causing acute testicular damage in male rats also caused significant creatinuria and creatinaemia at 48 h after dosing. Doses of cadmium which did not cause testicular necrosis did not cause creatinuria or creatinaemia. Surgical ligation of the pampiniform plexus also caused ischaemic necrosis of the testis and this was followed by significant creatinuria and creatinaemia. However, neither orchidectomy followed by a toxic dose of cadmium, orchidectomy alone nor sham operation caused significant creatinuria or creatinaemia. Cadmium dosing induced a temporary loss of body weight which was less than that caused by food restriction. Food restriction did not cause significant creatinuria but did cause significant creatinaemia. These data suggest that the creatine is derived from the damaged testis and that measurement of urinary creatine may be a useful non-invasive means of detecting acute testicular damage caused by exposure to chemicals or mechanical impairment of blood flow.Archive für Toxikologie 01/1990; 64(6):443-450. · 5.22 Impact Factor
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ABSTRACT: 1. This study assessed urinary creatine excretion as a marker for testicular atrophy. 2. Male rats received a single i.p. dose of 2-methoxyethanol at 0, 250 or 750 mg kg-1 and were sacrificed 2 d later. Urinary creatine and creatinine excretion were measured on days 0, 1 and 2. 3. Decreased testicular weights and histopathological assessment revealed dose-related testicular damage. 4. On day 1, at both doses of 2-methoxyethanol, urinary creatine levels increased and creatinine levels decreased, resulting in a dose-related increase in the creatine/creatinine ratio. On day 2, the creatine/creatinine ratio was elevated relative to controls, but was less marked than on day 1. 5. The study confirmed that creatine excretion is a potential marker for acute testicular damage.Human & Experimental Toxicology 04/1993; 12(2):173-6. · 1.45 Impact Factor