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)

Acetaminophen is eliminated primarily by glucuronidation, thereby avoiding cytochrome P450-catalyzed bioactivation to a toxic reactive intermediate. Previous studies have shown that UDP-glucuronosyltransferase-deficient Gunn rats are more susceptible to acetaminophen toxicity than normal Wistar controls, from which the Gunn strain was derived. However, the Gunn and Wistar strains are not congenic, and differences in toxicologic susceptibility could be due in part to genetic differences other than UDP-glucuronosyltransferase activity. Accordingly, acetaminophen (750 mg/kg, ip) was administered to congenic RHA rats with normal (homozygous, RHA/++), moderately deficient (heterozygous, RHA/j+), and severely deficient (homozygous jaundiced, RHA/jj) activities of bilirubin UDP-glucuronosyltransferase. Acetaminophen metabolites were measured by high-performance liquid chromatography and production of the acetaminophen glucuronide conjugate was quantified by the area under plasma concentration-time curve (AUC) from 0 to 2 hr, standardized by the AUC value for acetaminophen in the same animal (glucuronidation ratio = AUC acetaminophen glucuronide/AUC acetaminophen). The 0- to 2-hr time period for AUC calculations was necessitated by the accumulation at later time points of glucuronide and sulfate conjugates in the plasma of animals experiencing severe nephrotoxicity. Acetaminophen bioactivation was quantified by the 24-hr urinary recovery of glutathione-derived conjugates. Hepatotoxicity and nephrotoxicity were assessed respectively by the peak concentrations of plasma alanine aminotransferase (ALT) and blood urea nitrogen (BUN). Glucuronidation of acetaminophen in RHA/jj rats (0.065 +/- 0.005) (mean +/- SE) was reduced 63% compared to the RHA/++ controls (0.17 +/- 0.01) (p < 0.05). RHA/jj rats demonstrated respective 230- and 7-fold increases in the peak plasma concentrations of ALT (17144 +/- 1014 vs 75 +/- 10) and BUN (128 +/- 23 vs 18.4 +/- 0.2) compared to congenic normal controls (RHA/++) (p < 0.05). Heterozygous animals (RHA/j+) demonstrated intermediary toxicity for both parameters (ALT = 2029 +/- 1581, BUN = 41 +/- 16, p < 0.05). Decreased glucuronide production correlated with elevations in ALT (r = -0.86, p < 0.001), while increased acetaminophen bioactivation correlated directly with both elevated ALT (r = 0.93, p < 0.001) and BUN (r = 0.83, p = 0.001). These results using congenic controls demonstrate that the enhanced susceptibility of UDP-glucuronosyltransferase-deficient rats to acetaminophen toxicity is due to decreased glucuronidation resulting in enhanced bioactivation, rather than to other unappreciated genetic differences.
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PMID:Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase. 144 Jun 17

Overdosage of acetaminophen (AA) is known to produce acute liver toxicity in both humans and laboratory animals. Hamsters are especially sensitive to the hepatotoxic effect of AA. In the present study, hamsters pretreated with pregnenolone-16 alpha-carbonitrile (PCN; 75 mg/kg, ip, daily for 4 days) were given a single dose of AA (350-1200 mg/kg, ip) and liver function was determined 24 hr later. Serum activities of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) as well as histopathology were used as indices of hepatotoxicity. PCN pretreatment decreased AA-induced mortality. PCN dramatically decreased ALT (93-97%) and SDH (63-98%) activities relative to control values from hamsters treated with AA alone, and remarkably decreased hepatic centrilobular necrosis produced by AA. To investigate the mechanism of this protective effect, the biliary and urinary excretion of AA metabolites were measured for 1 hr after administration of AA (150 mg/kg, iv) in bile-duct-cannulated hamsters. PCN pretreatment resulted in increased urinary and biliary excretion of AA-glucuronide and decreased biliary excretion of AA-glutathione. Microsomes from PCN-pretreated hamsters produced less benzoquinoneimine intermediate than controls, as determined by the formation of AA-glutathione. In addition, hepatic UDP-glucuronic acid and UDP-glucuronosyltransferase were significantly increased in PCN-pretreated hamsters. In conclusion, PCN pretreatment protected against AA-induced hepatotoxicity. The mechanism of this protection appears to be due to decreased formation of the reactive metabolite by the cytochrome P450 pathway, and an increased detoxication by enhanced glucuronidation of AA.
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PMID:Protective effect of pregnenolone-16 alpha-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters. 206 28

Intact periportal (pp) or perivenous (pv) hepatocytes were prepared by digitonin-collagenase liver perfusion. The degree of separation was indicated by significant differences between the pp and pv cells in their activity of the pp markers, alanine aminotransferase (pp/pv = 2.1), gamma-glutamyltranspeptidase (3.4) and lactate dehydrogenase (1.3), and of the pv markers, glutamate dehydrogenase (0.73) and pyruvate kinase (0.81). This pattern was not altered by a 3-day pretreatment with phenobarbital (PB). The hepatocytes isolated from the pv area contained higher activities of microsomal NADPH-cytochrome c reductase, 7-ethoxycoumarin O-deethylase, 7-ethoxyresorufin O-deethylase and benzo(a)pyrene hydroxylase, and of cytosolic glutathione transferase. Cytochrome P-450 and UDP-glucuronosyltransferase were slightly higher in pv cells. Treatment with PB induced NADPH-cytochrome c reductase, glutathione transferase, cytochrome P-450 and UDP-glucuronosyltransferase but the degree of induction was found to be at least as strong in pp cells as in pv cells. The induction of 7-ethoxyresorufin O-deethylase and 7-ethoxycoumarin O-deethylase was clearly more prominent in pp cells. On the other hand, PB reduced the activities of benzo(a)pyrene hydroxylase and alcohol dehydrogenase in both cell types. These results demonstrate by direct enzyme assay of separated cells the dominance of the pv-region for metabolizing drugs in the normal liver. Contrary to several other studies, however, our data indicate that induction by PB occurs panacinarily, i.e., relatively more in the pp region, thus diminishing rather than exaggerating the original pv dominance.
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PMID:Effect of phenobarbital on the distribution of drug metabolizing enzymes between periportal and perivenous rat hepatocytes prepared by digitonin-collagenase liver perfusion. 302 20

Human gamma interferon given for up to 5 days by subcutaneous infusion or intraperitoneal injection did not significantly alter mouse hepatic microsomal oxidative drug-metabolizing enzyme activities. In contrast, murine gamma interferon and human alpha interferon given for 5 days at the same dose (10(7) units/kg) caused 25 and 50% decreases, respectively, in hepatic microsomal cytochrome P-450 concentrations. The human alpha interferon-induced decline in cytochrome P-450 was accompanied by a significant drop in p-nitroanisole demethylase activity and significant elevations in serum alanine aminotransferase and cytosolic glutathione S-transferase activities. An elevation in glutathione-S-transferase was the only significant change found following human gamma interferon administration. Microsomal UDP-glucuronosyltransferase activity was unaffected by any interferon.
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PMID:The influence of recombinant DNA-derived human and murine gamma interferons on mouse hepatic drug metabolism. 308 59

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

Murine IFN(gamma) and human IFN(alpha)-AD:Bgl were compared over a limited dose range and after single and multiple dosing for their effect on male mouse liver oxidative and conjugative drug metabolizing enzymes. Both IFNs depressed the microsomal cytochrome P-450 concentration but did not alter cytosolic glutathione S-transferase nor microsomal UDP-glucuronosyltransferase activity. Both IFNs showed some slight hepatotoxicity (elevated serum ALT), alpha AD:Bgl more than gamma, especially after multiple dosing. While the IFNs did not produce significant increases in liver weight, they did increase the yield of microsomal protein. The increased endoplasmic reticulum may compensate for the decreased cytochrome P-450 concentration and so account for the lack of observed effect of the IFNs on hexobarbital sleep times in vivo. Overall, the minimal effects of murine gamma-IFN on the mouse liver were no different than those of human alpha AD:Bgl.
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PMID:Effect of murine gamma-interferon on the mouse liver and its drug-metabolizing enzymes: comparison with human hybrid alpha-interferon. 392 33

Intraperitoneal injection (50 mg/kg) of 2-nitropropane (2-NP) induced lipid accumulation, centrilobular necrosis, degranulation of rough endoplasmic reticulum, proliferation of smooth endoplasmic reticulum and mitochondrial abnormalities in rat liver 24 h after exposure. These pathological changes were accompanied by elevated serum alanine aminotransferase (ALAT) levels. Hepatic glutathione content increased rapidly in exposed rats. 2-NP depressed markedly hepatic cytochrome P-450 and microsomal monooxygenase activity while the enzyme, epoxide hydratase, UDP-glucuronosyltransferase and cytosolic glutathione peroxidase were enhanced. 2-NP caused an increase of acetylcholine esterase activity in the brain. This effect was also detected in synaptosomes isolated from exposed rats. The results suggest peroxidative damage in the cells.
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PMID:Acute effects of 2-nitropropane on rat liver and brain. 731 30

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.
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PMID:Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines. 981 87

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

There is a possibility that serious liver dysfunction rarely observed in diabetic patients given troglitazone is attributable to idiosyncratic abnormalities in liver drug-metabolism. In addition, the results of blood biochemical examinations in serious cases of liver dysfunction showed a tendency for a high level of total bilirubin (T-Bil) over a long period compared with other indicators of liver dysfunction. Thus, we focused on genetic variation of UDP-glucuronosyltransferases (UGTs) that are involved in the conjugation of troglitazone and bilirubin. In this study, Gunn rats, which are hereditarily deficient in the UGT1 family of UGT isozymes, and Wistar rats, the parent strain of Gunn rats, were treated with troglitazone for 3 months at dose levels of 0, 100 or 400 mg/kg to investigate two possibilities: first, whether the genetic deficiency in UGT1s induces an alteration of the metabolic profile of troglitazone followed by liver dysfunction, and second, whether the dosing of troglitazone to Gunn rats which show hyperbilirubinemia result in liver dysfunction. As a result, the metabolic profile of troglitazone in Gunn rats was much the same as that of Wistar rats, suggesting that genetic deficiencies in UGT1s did not influence the metabolic profile of troglitazone. Moreover, no elevation of blood biochemical parameters, such as asparate aminotransferase (AST) and alanine aminotransferase (ALT), or histopathological liver injuries, such as hepatocellular degeneration and necrosis, were observed in either strain of rats, and hyperbilirubinemia in Gunn rats was not aggravated by the dosing of troglitazone. These results strongly suggest that troglitazone was not metabolized by UGT1s but by other UGT isozyme (s) in rats, and that glucuronidation of troglitazone did not compete with glucuronidation of bilirubin in vivo. Thus, it is suggested that high levels of total bilirubin in patients with liver dysfunction induced by troglitazone are attributable to hypofunction due to hepatocellular injury, not to metabolic competition of bilirubin with troglitazone. Moreover, it is also suggested that the deficiency in the UGT1 family of UGT isozymes itself may not be the cause of liver dysfunction associated with troglitazone treatment.
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PMID:Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism. 1120 Nov 73


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