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)

The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho-DCB (o-DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three endpoints, meta-DCB (m-DCB) exhibited a lesser toxicity. Para-DCB (p-DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m-DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p-DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o-DCB and p-DCB were administered at dosages several times the oral rat LD-50 (RTECS) without any lethality.
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PMID:The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene. 129 13

We report the development of severe hepatotoxicity in a patient on zidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient's serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 mumol/L. These values substantially improved over the ensuing 4 days. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus were all negative. The pattern and time sequence of transaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since zidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesize that our patient's susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as zidovudine and/or trimethoprim-sulfamethoxazole with subsequent increased cytochrome P450-dependent metabolism of acetaminophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the P450 system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving zidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when taking both these medications.
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PMID:Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. 836 34

Recently, we demonstrated that a microsomal enzyme inducer with a steroidal structure, pregnenolone-16 alpha-carbonitrile (PCN), markedly decreased the hepatotoxicity of acetaminophen (AA) in hamsters. Therefore, it was of interest to determine if PCN, as well as another steroid microsomal enzyme inducer, dexamethasone (DEX), would decrease the toxicity of AA in mice, another species sensitive to AA hepatotoxicity. Mice were pretreated with PCN or DEX (100 and 75 mg/kg, ip, for 4 days, respectively) and were given AA (300-500 mg/kg, ip). Twenty-four hours after AA administration, liver injury was assessed by measuring serum activities of sorbitol dehydrogenase and alanine aminotransferase and by histopathological examination. Neither PCN nor DEX protected markedly against AA hepatotoxicity in mice; PCN tended to decrease AA-induced hepatotoxicity, whereas DEX was found to enhance AA-induced hepatotoxicity and it produced some hepatotoxicity itself. DEX decreased the glutathione concentration (36%) in liver and increased the biliary excretion of AA-GSH, which reflects the activation of AA, whereas PCN produced neither effect. Thus, whereas PCN has been shown to markedly decrease the hepatotoxicity of AA in hamsters, apparently by decreasing the isoform of P450 responsible for activating AA to N-acetyl-p-benzoquinoneimine, this does not occur in mice after induction with either PCN or DEX. In contrast, DEX enhances AA hepatotoxicity apparently by decreasing liver GSH levels and increasing the activation of AA to a cytotoxic metabolite.
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PMID:Effect of pregnenolone-16 alpha-carbonitrile and dexamethasone on acetaminophen-induced hepatotoxicity in mice. 164 53

The destruction of liver microsomal cytochromes P450 by a previously administered low dose of CCl4 has been widely accepted as the mechanism of CCl4 autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl4 (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, po) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P450 (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl2 to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl4. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl4. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following 3H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl4, stimulated nuclear DNA synthesis measured by 3H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl4. Forty-eight hr after the administration of a lethal dose of CCl4 alone (5 ml/kg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl4. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CC14.
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PMID:Role of hepatocellular regeneration in CCl4 autoprotection. 204 7

Acetaminophen hepatotoxicity is associated with its biotransformation to the reactive metabolite N-acetyl-p-benzoquinone imine that binds to protein. Two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated as primarily responsible for the bioactivation. To determine the relative contributions of these P450's, overnight fasted male NMRI mice were pretreated with 10 ml of 50% v/w propylene glycol/kg or fluvoxamine (10 mg/kg) at -80 and -20 min. relative to acetaminophen dosing to inhibit CYP2E1 and CYP1A2, respectively. Mice were sacrificed at 0.5 or 4 hr after a hepatotoxic dose of acetaminophen (300 mg/kg). Propylene glycol or propylene glycol plus fluvoxamine, but not fluvoxamine alone protected against acetaminophen hepatotoxicity as indicated by abolished increase in serum alanine aminotransferase activity, less depletion of hepatic glutathione and lower liver:body weight ratios. Propylene glycol inhibited the activity of CYP2E1 as indicated by 84% reduction in the clearance of 3 mg/kg dose of chlorzoxazone, whereas fluvoxamine inhibited the activity of CYP1A2 as indicated by 40% reduction in the clearance of a 10 mg/kg dose of caffeine. For this animal model, the data are consistent with the notion that hepatoxicity is associated with bioactivation of acetaminophen by CYP2E1 but not by CYP1A2.
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PMID:Cytochrome P4502E1 inhibition by propylene glycol prevents acetaminophen (paracetamol) hepatotoxicity in mice without cytochrome P4501A2 inhibition. 747 82

3,5-Dichloroaniline (3,5-DCA), a derivative needed in the manufacture of dyes, pesticides and industrial compounds has been reported to induce renal damage. This study investigated whether pretreatment with inducers or inhibitors of P450 altered 3,5-DCA toxicity. P450 levels were induced in male Fischer 344 rats (4-12/group) by pretreatment (i.p.) with phenobarbital (PB, 75 mg/kg/day for 3 days), beta-naphthoflavone (BNF, 100 mg/kg/day for 4 days) or pyridine (PYR, 100 mg/kg/day for 4 days). P450 activity was inhibited by pretreatment with piperonyl butoxide (PiBx) 30 min prior to injection of 3,5-DCA. Upon completion of a designated pretreatment regimen, 0.4 or 0.8 mmol/kg 3,5-DCA was injected into F344 rats. Pair-fed controls were injected with 25% ethanol solution or physiological saline (2.5 ml/kg). The renal changes monitored at 24 and 48 h following treatment with 0.8 mmol/kg 3,5-DCA were characterized by increased blood urea nitrogen (BUN) level and decreased renal cortical slice accumulation of p-aminohippurate (PAH). Plasma alanine transaminase activity (ALT/GPT) was increased 24 h after injection of 0.8 mmol/kg 3,5-DCA while liver wt. was unchanged. PB or PYR pretreatment did not alter the renal or hepatic effects of 3,5-DCA while BNF pretreatment slightly reduced toxicity. In contrast, PiBx pretreatment increased the renal and hepatic changes associated with 3,5-DCA. The results with PiBx suggest that either the parent compound possesses some direct cytotoxicity or that a toxic metabolite was generated through a biotransformation pathway not inhibited by PiBx.
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PMID:3,5-Dichloroaniline toxicity in Fischer 344 rats pretreated with inhibitors and inducers of cytochrome P450. 762 91

The hepatotoxicity of the herbal plant germander and that of one of its major furanoneoclerodane diterpenes, teucrin A, were investigated in mice. Teucrin A was found to cause the same midzonal hepatic necrosis as observed with extracts of the powedered plant material. Evidence that bioactivation of teucrin A by cytochromes P450 (P450) to a reactive metabolite(s) is required for initiation of the hepatocellular damage is provided by results of experiments on the induction and inhibition of P450 and from studies on the effects of glutathione depletion. Pretreatment of mice with the P450 inducer phenobarbital enhanced the hepatotoxic response, as indicated by an increase in plasma alanine aminotransferase (ALT) levels and hepatic necrosis, while pretreatment with the P450 inhibitor piperonyl butoxide markedly attenuated the toxic response. Hepatotoxicity of teucrin A also was increased following pretreatment with the inhibitor of glutathione synthesis buthionine sulfoximine. Most importantly, the tetrahydrofuran analog of teucrin A, obtained by selective chemical reduction of the furan ring, was not hepatotoxic, a result that provides strong evidence that oxidation of the furan ring moiety of the neoclerodane diterpenes is involved in the initiation of hepatocellular injury caused by germander.
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PMID:Hepatotoxicity of germander (Teucrium chamaedrys L.) and one of its constituent neoclerodane diterpenes teucrin A in the mouse. 769 42

The carcinogenic water disinfection byproduct, bromodichloromethane (BDCM), produces renal and hepatic toxicity in rodents in acute and subchronic studies. In the present investigation, female rats and mice (n = 6) were dosed daily for 5 consecutive days with BDCM (dissolved in an aqueous, 10% Emulphor solution) by gavage. Rats received 75, 150 and 300 mg BDCM/kg body weight/day and mice received 75 and 150 mg BDCM/kg body weight/day. Two rats in the 300 mg/kg/day treatment group died on day 5. On day 6, the animals were sacrificed and serum samples were taken for analysis of indicators of hepatic and renal toxicity. Livers and kidneys were excised and samples taken for histopathological evaluation. Portions of the livers were also utilized to produce microsomes for analysis of cytochrome P450 enzyme activities and total P450 content. Total hepatic cytochrome P450 was decreased in rats dosed with 150 and 300 mg BDCM/kg body weight/day, but was not significantly affected in BDCM-treated mice. Serum lactate (LDH) and sorbitol (SDH) dehydrogenase, aspartate aminotransferase (AST), creatinine and blood urea nitrogen were increased above those of controls in rats dosed with 300 mg BDCM/kg/day. These data suggested that hepatic and renal damage had occurred in this treatment group. This was confirmed by histopathological analyses which revealed that lesions occurred in both hepatic and renal tissues from rats dosed with 150 and 300 mg BDCM/kg/day. The hepatic lesions were centrilobular and primarily consisted of vacuolar degeneration. The hepatotoxicity indicators alanine aminotransferase (ALT) and SDH were increased in mice dosed with 150 mg BDCM/kg/day. However, no histopathological lesions were observed in these animals. This study shows that BDCM is both hepatotoxic and nephrotoxic to female rats after repeated dosing, but is only weakly hepatotoxic to female mice at the administered doses. Also, reduced activities of hepatic cytochrome P450 were observed in rats, but not mice. These species differences in toxicity and xenobiotic metabolizing enzyme inhibition caused by BDCM suggest that an understanding of the mechanism of toxicity of this compound will be critical when extrapolating rodent toxicity data to humans for this environmental pollutant.
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PMID:Toxicity of bromodichloromethane in female rats and mice after repeated oral dosing. 780 27

Chemical activation of Kupffer cells in vivo by vitamin A or latex beads is associated with a worsening of hepatic injury induced by the P450-dependent hepatotoxins acetaminophen (ACET) and carbon tetrachloride (CCl4) and by the P450-independent toxin galactosamine (GLN). Immunostimulants such as Corynebacterium parvum (CP) also activate Kupffer cells, but do so while prompting release of soluble mediators which depress microsomal oxidative activities in cultured hepatocytes. Therefore, we sought to characterize the effects of CP on hepatic injury in vivo due to ACET and CCl4 while employing GLN as a control. Hepatic microsomal oxidative activity and glutathione (GSH) disposition were examined since each influences susceptibility to injury from ACET or CCl4. Rats were given CP 28 mg/kg i.v. 5 days before challenge with hepatotoxicant. Hepatic injury was assessed 24 hr after hepatotoxicant administration by measurement of serum alanine aminotransferase (ALT) activity and review of histological sections. Livers from parallel groups of rats were used to prepare microsomal and cytosolic fractions, to measure tissue GSH, or for perfusion to assess GSH efflux. Significant reductions in injury due to ACET or CCl4 were observed while injury due to GLN was potentiated. Serum ALT levels after ACET were 3000 +/- 620 in controls vs 170 +/- 45 IU/liter in the CP-treated group and ALT levels after CCl4 were 3100 +/- 500 in controls vs 1700 + 450 IU/liter in the CP-treated group. In contrast, serum ALT levels after GLN were 920 +/- 230 in controls vs 1700 +/- 370 in the CP-treated group. Patterns of hepatic injury observed on histological sections were those characteristic for each toxin and the severity of injury correlated well with alterations in serum ALT levels for each agent. Hepatic microsomal fractions from rats pretreated with CP showed significantly diminished total cytochrome P450 content as well as reduced activity for two P450IIE1 substrates, p-nitrophenol and 7-ethoxycoumarin. While sinusoidal efflux of GSH increased by 40% in rats pretreated with CP and cytosolic glutathione-S-transferase activity fell slightly, tissue GSH levels were unaffected. These data demonstrate that CP decreases microsomal cytochrome P450 content, reduces biotransformation of two P450IIE1 substrates, and diminishes ACET- and CCl4-induced hepatic injury. In contrast, hepatic injury due to the P450-independent toxin GLN was enhanced. Thus, chemical and immune stimulation of Kupffer cells may result in divergent effects on susceptibility to injury from individual hepatotoxins.
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PMID:Kupffer cell stimulation with Corynebacterium parvum reduces some cytochrome P450-dependent activities and diminishes acetaminophen and carbon tetrachloride-induced liver injury in the rat. 797 94

This study examined the contribution of biotransformation by the mixed function oxidase system on hepatic and renal toxicity of 1,2-dichlorobenzene (1,2-DCB). Male Fischer 344 (F344) rats (190-250 g) were pretreated with phenobarbital (PB), beta-naphthoflavone (BNF), pyridine (PYR), piperonyl butoxide (PiBx) or vehicle prior to the administration of 2 or 3 mmol/kg of 1,2-DCB. Pair-fed control animals were treated with corn oil, (1 ml/kg). Plasma alanine amino-transaminase (ALT/GPT) was increased in a dose-dependent manner by 1,2-DCB. Pretreatment with PB, BNF or PB pretreatment prior to 1,2-DCB administration increased hepatic toxicity within 24 h. Toxicity was characterized by increased ALT/GPT activity and increased liver weight. Acute administration of 1,2-DCB produced renal alterations within 24 h. Renal toxicity was characterized by altered blood urea nitrogen (BUN) concentration and decreased renal cortical slice accumulation of p-aminohippurate (PAH) 24 h after injection of 3 mmol/kg 1,2-DCB. Pretreatment with PB, BNF or PYR increased the renal toxicity of 2 and 3 mmol/kg 1,2-DCB. Conversely, pretreatment with PiBx to inhibit P450 activity slightly decreased the hepatic and renal toxicity of 1,2-DCB. These results establish that the kidney was a target organ for 1,2-DCB toxicity and that the proximal tubule was a site of damage. Additionally, these studies indicate induction of P450 isozymes increased the hepatic and renal toxicity of 1,2-DCB. Further studies are needed to examine the specific role of P450 in generation of toxicity.
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PMID:Modification of P450 activity and its effect on 1,2-dichlorobenzene toxicity in Fischer 344 rats. 831 47


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