Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies, we reported that the age-dependent hepatotoxicity of galactosamine (GalN) was evident in hepatocytes maintained in primary cultures. Cellular proliferation and tissue repair are not manifested in response to injury in this in vitro system. Neonatal (5-day) rats have ongoing hepatocellular proliferation in contrast to adult (5-month) rats, and should be therefore resilient to GalN toxicity. Liver injury was assessed by serum transaminases (ALT, AST), 3H-thymidine (3H-T) incorporation into nuclear DNA, and content of hepatocellular nuclear DNA. While the dose of 400 mg/kg did not cause any significant liver injury in the neonates, it did produce significant liver injury in adult rats. At a dose of 800 mg/kg, GalN produced significant injury in the neonates. Because 400 mg/kg causes clearly demonstrable liver injury in the adult and no injury in the neonates, this dose was used for further studies. In addition to the above measures of injury, uracil nucleotides (UTP, UDP, and UMP), glycogen, histopathology, and autoradiographic examination of liver sections were used to assess the liver injury in neonatal and adult rats. In a time-course study, all of the above were measured at 0, 12, 24, 36, 48 and 72 h after GalN administration. Serum enzyme elevations as well as the appearance of necrotic and swollen hepatocytes were maximal at 24 h in the adults rats. In contrast to these observations in the adult rats, none of these measurements indicated significant liver injury in the neonates. 3H-T incorporation into nuclear DNA was much higher in the neonatal liver in comparison to the adults reflecting the difference in regeneration. Hepatocellular nuclear DNA was also higher in the neonate and was significantly decreased due to GalN treatment. In the adult rats, the quiescent normal level of 3H-T incorporation and nuclear DNA content were further decreased at 12 h, increased at 48 h and returned to normal low, quiescent levels at 72 h. In the neonates mitotic activity of hepatocytes was higher than in the adult rats. In the adult rats, mitotic activity was increased at 48 h after GalN administration and returned to normal at 72 h. In the neonates GalN did not alter the mitotic activity significantly. These findings demonstrate that in the presence of hepatocellular regeneration, galactosamine toxicity is minimal while in the absence of it, clear toxicity is manifested. In conclusion, while perturbation in uracil nucleotides and related biochemical events may explain the infliction of liver injury by GalN in an age-dependent fashion, the extent of tissue repair impacts decisively on the final outcome of injury.
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PMID:Ongoing hepatocellular regeneration and resiliency toward galactosamine hepatotoxicity. 129 Apr 5

Glucuronidation is the major pathway for elimination of acetaminophen, diverting it from the toxifying pathway catalyzed by cytochromes P-450. A genetic deficiency in bilirubin UDP-glucuronyl transferase may predispose humans and animals to the toxicity of drugs that are extensively glucuronidated, if other glucuronyl transferase isoenzymes are concurrently deficient. Homozygous and heterozygous Gunn rats are, respectively, severely and moderately deficient in glucuronyl transferase. Acetaminophen (500 mg per kg) was administered intraperitoneally to homozygous and heterozygous Gunn rats and to Wistar controls. Hepatic and renal cellular damage was assessed by peak plasma concentrations of ALT and blood urea nitrogen, respectively. Homozygous and heterozygous Gunn rats showed, respectively, 115-fold and 9-fold higher ALT concentrations compared to Wistar controls. Blood urea nitrogen was elevated only in the homozygous Gunn rats (3-fold). Biotransformation of acetaminophen was measured by high-performance liquid chromatography. Acetaminophen glucuronidation was decreased by 72 and 35% (p less than 0.05), respectively, in the homozygous and heterozygous Gunn rats compared with Wistar controls. Production of acetaminophen glucuronide correlated negatively with ALT concentration (r = -0.89, p less than 0.001). Production of glutathione-derived metabolites, reflecting acetaminophen bioactivation, was 2 to 3-fold higher in the Gunn rats (p less than 0.05) and correlated with ALT concentrations (r = 0.90, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency. 250 Dec 10

Over 60% of the analgesic/antipyretic drug acetaminophen is eliminated by glucuronidation, which competes with a toxifying pathway involving cytochromes P-450-catalyzed bioactivation to a hepatotoxic reactive intermediate. A genetic deficiency of bilirubin UDP-glucuronyl transferase (GT) occurs in 5 to 7% of the population (Gilbert's disease, Crigler-Najjar syndrome) and this could predispose such people to acetaminophen hepatotoxicity. This hypothesis was evaluated in the homozygous Gunn rat, which is similarly deficient in GT, and the heterozygous Gunn rat, which has intermediary GT activity. Acetaminophen, 1 g/kg, was administered by gavage to animals 6 and 11 weeks of age, and age-matched Wistar rats as controls. Hepatic and renal cellular damage were assessed by respective increases in the peak plasma concentration of alanine aminotransferase and the blood urea nitrogen concentration, and confirmed by histological examination. Acetaminophen and metabolites were measured by high-performance liquid chromatography. Compared to Wistar controls, Gunn rats demonstrated up to a 110-fold greater hepatotoxic response to acetaminophen, with significantly lower production of the glucuronide conjugate and higher plasma concentrations of acetaminophen. Elevated acetaminophen concentrations correlated positively with both increased production of the acetaminophen-cysteine conjugate, reflecting bioactivation and hepatotoxicity. Older Gunn but not Wistar rats showed up to 26-fold more hepatotoxicity compared to their younger counterparts. In younger animals, heterozygotes demonstrated intermediary hepatotoxicity between homozygotes and Wistar controls. Hepatotoxicity was similar in the older heterozygotic and homozygotic Gunn rats, as was renal toxicity, which was enhanced 2- to 3-fold over controls. These results indicate that a genetic deficiency in bilirubin GT can be an important determinant of acetaminophen bioactivation and toxicity.
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PMID:Deficiency in bilirubin UDP-glucuronyl transferase as a genetic determinant of acetaminophen toxicity. 313 68

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.
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PMID:The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats. 335 67

Rats were treated with 50 mg phenobarbital (PB) per kg body weight for 7 days prior to or after partial hepatectomy. The activities of aspartate aminotransferase, alanine aminotransferase, and glutamate dehydrogenase were measured in the regenerating liver 1 week following liver amputation. UDP-glucuronyl transferase activity was determined at the time of surgery as well as 7 days later at the time of death. Alanine aminotransferase was induced by PB in rats only treated in the postoperative period, while aspartate aminotransferase and glutamate dehydrogenase were not. The activity of UDP-glucuronyl transferase was increased more than twofold by repeated PB treatment in both normal and regenerating liver. After cessation of therapy, however, the enhanced activities returned to a normal level. It is concluded that UDP-glucuronyl transferase activity in regenerating liver is as inducible as in normal rat liver by repeated PB treatment despite incomplete hepatic regeneration. Preoperative PB treatment alone is not sufficient to stimulate the glucuronylating pathway in the late phase of liver regeneration.
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PMID:Late phase of liver restoration following partial hepatectomy in phenobarbital-treated rats. II. Effect of phenobarbital on aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase, and UDP-glucuronyltransferase activity. 640 78

As part of a six-month prospective study of the effects of neonatal thymectomy in the spontaneously diabetic BB Wistar rat, activities of the following enzymes were determined: alkaline phosphatase (AP), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and UDP-galactosyltransferase (UDPG). In prediabetics, AP and LDH levels were higher than in sham-operated, non-diabetic controls; however, this increase was seen in nearly all diabetes-prone BB rats, diminishing the usefulness of these changes in discerning potential diabetics from asymptomatic, diabetes-prone rats. After onset of the syndrome, there was a striking elevation of AP values in all diabetics with no similar alteration in asymptomatic, diabetes-prone rats suggesting this was a diabetes-related phenomenon. By contrast, UDPG was the only enzyme to decrease immediately following the onset of the syndrome. Both UDPG and AP levels correlated with blood glucose, the former negatively and the latter positively, suggesting a close relationship with changes occurring after onset of the syndrome. The remaining enzymes increased only in a portion of diabetics alone (GOT, GPT) or in a portion of both diabetics and asymptomatic, diabetes-prone BB rats (LDH, CPK).
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PMID:Serum enzymes in the BB rat before and after onset of the overt diabetic syndrome. 643 99

Wistar male rats were exposed by inhalation to 50, 100 or 400 ppm of ethylene glycol monomethyl ether (EGME) for 1 to 2 weeks. The overall hepatic drug oxidation reactions, O-deethylation of 7-ethoxycoumarin and 7-ethoxyresorufin and cytochrome P-450 content were only slightly affected by the EGME exposures. NADPH cytochrome c reductase activity showed a tendency toward a dose-dependent decrease in liver, the activity being 73% and 64% of that in the controls after one and two weeks of exposure, at 400 ppm respectively. UDP glucuronosyl transferase activity exhibited a dose-dependent enhancement in liver microsomes after exposure for two weeks to EGME. The enhancement was 1.3- 1.7- and 3.0 fold with exposure to 50, 100 and 400 ppm of EGME respectively. After exposure for one week the UDPglucuronosyltransferase activity in kidney microsomes was similarly enhanced. A dose-related increase in measurable UDPglucuronosyltransferase activity was also obtained in Triton X-100 treated hepatic microsomes. GSH levels of the liver and kidneys in EGME treated animals showed a tendency towards a dose-dependent increase. The activities of low-Km and high-Km aldehyde dehydrogenases in liver were decreased 6 - 14% of that in the controls with exposure to 400 ppm of EGME when glycolaldehyde was used as a substrate. Serum alanine aminotransferase activity was not influenced by inhalation exposures to EGME.
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PMID:Dose-dependent toxicity of ethylene glycol monomethyl ether vapour in the rat. 680 Jul 97

The hepatoprotective effect of carsil (generic name silymarin) on a model of liver intoxication with D-galactosamine in rats is studied. The changes in the activity of the serum enzymes GOT, GPT, MDH, SDH, ICDH, AP. AhE and the total protein as well as the UDP-sugars content in the liver is investigated. Histochemical and electronmicroscopical investigations of the liver are carried out simultaneously. It is obvious that carsil prevents to a considerable degree the increase of the serum enzymes activity caused by a D-galactosamine injury, enhances the metabolic conversion of the UDP-hexosamine into UDP-acetylhexosamine in the liver and hastens the normalizing of the UDP-glucuronic acid content in the liver of rats. The biochemical and morphological changes under the influence of carsil and the possible biochemical mechanism of the drug action is discussed.
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PMID:Hepatoprotective effect of silymarin (carsil) on liver of D-galactosamine treated rats. Biochemical and morphological investigations. 723 Sep 79

Nrf2, which belongs to the basic leucine zipper (bZip) transcription factor family, has been implicated as a key molecule involved in antioxidant-responsive element (ARE)-mediated gene expression. In order to examine the role of Nrf2 in protection against xenobiotic toxicity, the sensitivity of nrf2 knockout mice to acetaminophen (N-acetyl-4-aminophenol (APAP)) was analyzed. The saturation of detoxification pathways after high levels of exposure to APAP is known to induce hepatotoxicity. Two factors important in its detoxification are UDP-glucuronosyltransferase (UDP-GT), an ARE-regulated phase-II drug-metabolizing enzyme, and glutathione (GSH), an antioxidant molecule whose synthesis depends on ARE-regulated gamma-glutamylcysteine synthetase (gammaGCS). Two- to 4-month-old male mice were orally administered a single dose of APAP at 0, 150, 300, or 600 mg/kg. Doses of 300 mg/kg APAP or greater caused death in the homozygous knockout mice only, and those that survived showed a greater severity in hepatic damage than the wild-type mice, as demonstrated by increased plasma alanine aminotransferase activity, decreased hepatic non-protein sulfhydryl (NPSH) content, and centrilobular hepatocellular necrosis. The high sensitivity of Nrf2-deficient mice was confirmed from observations made at 0, 2, 8, and 24 h after dosing with 300 mg/kg APAP; increased anti-APAP immunoreactivity was also noted in their livers at 2 h. Untreated homozygous knockout mice showed both a lower UDP-GT activity and NPSH content, which corresponded to decreased mRNA levels of UDP-GT (Ugt1a6) and the heavy chain of gammaGCS, respectively. These results show that Nrf2 plays a protective role against APAP hepatotoxicity by regulating both drug metabolizing enzymes and antioxidant genes through the ARE.
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PMID:High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. 1113 56

Benzothiazole (BT) is present in tobacco smoke and widely used for industrial and pharmaceutical purposes. In this study we have investigated the influence of BT on the activities of hepatic cytochrome P450 monooxygenases (P450s) and UDP-glucuronyltransferase (UDP-GT), sulphotransferase and glutathione-S-transferase (GST) in male Sprague-Dawley rats. We also examined if BT would change the metabolism and toxification of acetaminophen (AA) through modulation of metabolizing enzymes. Benzothiazole (1 mmol kg(-1), p.o., 5 days) markedly increased the enzyme activities of P4501A1, 1A2, 2B1, 3A4, 2E1, UDP-GT and GST in liver. Pretreatment with BT significantly decreased the amount of total AA recovered in bile to 68.5% of controls, mainly as a consequence of reduced AA-glucuronide conjugate (35.3% of controls), whereas the AA-glutathione conjugate (AA-GS) was augmented to 1.6-fold. After pretreatment with BT, potentiation of the hepatotoxicity by AA (400 mg kg(-1), i.p., 24 h) was observed by measuring serum alanine aminotransferase activities in ICR mice. These results indicate that: BT is a potent inducer of P450s and phase II metabolizing enzymes; and the increase of AA-GS conjugate and aggravation of AA hepatotoxicity by BT may be related to induction of P450s.
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PMID:Effects of benzothiazole on the xenobiotic metabolizing enzymes and metabolism of acetaminophen. 1118 Feb 62


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