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)

Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 mumol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53-2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in a dose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced by in vivo administration of 4-bromocatechol could not be distinguished histologically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and the 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.
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PMID:Nephrotoxicity of phenolic bromobenzene metabolites in the mouse. 671 May 48

The susceptibility of neonatal (11 days) and young rats (19 and 33 days) to acetaminophen-induced hepatic necrosis was examined. Acetaminophen-induced lethality (LD50) was slightly lower in 19-day-old animals (840 mg/kg) compared to 11- and 33-day-old animals (1220 and 1580 mg/kg, respectively). A toxic dose of the drug ( LD20 ) produced elevated serum glutamate-pyruvate transaminase and lactate dehydrogenase activities 20-24 hr after drug administration only in 19- and 33-day-old animals. Serum enzyme elevation was not observed after a toxic dose of acetaminophen ( LD20 or LD50) in 11-day-old rats. Histological evaluation showed that both 19- and 33-day-old rats developed extensive hepatic centrilobular damage, whereas morphological parameters in 11-day-old animals given acetaminophen were not different from controls. It appears that high doses of acetaminophen are lethal to young rats, but that 11-day-old animals are different from 19-day-old and older rats in that the neonatal animals lack susceptibility to the hepatotoxic effects of the drug. Lower susceptibility of the neonatal rat liver to the hepatic effects of two other hepatotoxicants (bromobenzene and tannic acid) was also observed.
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PMID:Hepatotoxicity of acetaminophen in neonatal and young rats. I. Age-related changes in susceptibility. 672 16

In this study, freshly prepared isolated rat hepatocytes were exposed to various concentrations of bromobenzene and six ortho-substituted bromobenzenes. Toxicity was estimated by trypan blue dye exclusion and release of GPT and K+ over a 0- to 4-hr time course. In all cases a close correlation among these three indices was observed. The rate of response depended on the exposure level and the nature of the o-substituent. The relative toxicity followed the order C2H5 greater than CH3 greater than or equal to CF3 greater than Br much greater than H greater than OCH3 much greater than CN. This order does not correlate well with the in vivo toxicity data previously obtained in this laboratory (Toranzo E. G., Gillesse, T., Mendenhall, M., Traiger, G.J., Riley, P.G., Hanzlik, R.P., and Wiley, R.A. (1977). Toxicol. Appl. Pharmacol. 40, 415-425.); in fact an almost inverse relationship is indicated. Several possible reasons are proposed in order to rationalize the discrepancy between these two results. The results emphasize the need for caution when using isolated hepatocytes to screen new compounds for purposes of determining their potential in vivo toxicity, at least until the differences between hepatocytes in vivo and hepatocytes in vitro are more thoroughly understood.
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PMID:Toxicity of ortho-substituted bromobenzenes to isolated hepatocytes: comparison to in vivo results. 685 88

Prior consumption of a diet containing the food antioxidant, butylated hydroxyanisole (BHA), by female mice prevented the development of or minimized the acute liver damage caused by monocrotaline, acetaminophen, or bromobenzene. In contrast, neither the incidence nor the severity of carbon tetrachloride-induced hepatotoxicity was affected by dietary BHA. Hepatotoxicity was judged by plasma alanine aminotransferase and aspartate aminotransferase levels, hepatic cytochrome P-450 content, and liver histology. The protective effect of BHA against acetaminophen-induced hepatotoxicity was not demonstrated in male mice. The observed protection by dietary BHA against acetaminophen- and bromobenzene-induced hepatotoxicity was associated with the increase of liver glutathione. It is concluded that the protective action of BHA is dependent upon the nature of the toxic agent.
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PMID:Protective role of dietary butylated hydroxyanisole against chemical-induced acute liver damage in mice. 685 90

Periportal or pericentral necrosis of rat liver was produced by injection of allyl-alcohol or bromobenzene, respectively. Activities of predominantly periportal and perivenous enzymes were determined in serum during maximal necrosis. Aspartate aminotransferase, which is more or less homogeneously distributed in the liver acinus, exhibited similar activities in serum after periportal and pericentral injury. Serum activities of the mainly periportal enzymes alanine aminotransferase and fructose 1,6-bisphosphatase were 1.5- to 2-fold higher after periportal as compared to pericentral necrosis. Serum activity of the mainly pericentral glutamate dehydrogenase was 3-fold higher after pericentral than after periportal damage. However, due to individual variations necrosis could not be definitively localized in any case by measurement of these enzyme activities. Better discrimination between periportal and pericentral necrosis was achieved by the serum activity of the exclusively pericentral enzyme glutamine synthetase, which was 8-fold higher after pericentral as compared to periportal necrosis. Conclusive discrimination was obtained by the activity ratio fructose 1,6-bisphosphatase/glutamine synthetase in serum.
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PMID:Discrimination between periportal and pericentral necrosis of rat liver by determination of glutamine synthetase and other enzyme activities in serum. 790 53

1. A series of flavonoids isolated from Indian medicinal plants: kaempferol-3-O-galactoside, hispidulin, nepetin, scutellarein, scutellarein-7-O-glucuronide, hibifolin and morelloflavone were studied for their activity as inhibitors of microsomal lipid peroxidation and scavengers of oxygen free radicals in vitro as well as in a model of xenobiotic toxicity in mouse. 2. All compounds inhibited lipid peroxidation in vitro. The most potent compounds were nepetin (non-enzymic lipid peroxidation) and morelloflavone (enzymic lipid peroxidation) with IC50's in the micromolar range. Some of the compounds behaved as scavengers of hydroxyl radical in the deoxyribose degradation assay, with a calculated rate constant for kaempferol-3-O-galactoside of 1.55 x 10(10) M-1 s-1. 3. Scutellarein and nepetin were found to be inhibitors of xanthine oxidase activity, whereas morelloflavone acted as a scavenger of superoxide generated by hypoxanthine/xanthine oxidase. 4. Treatment of mice with scutellarein, hispidulin, nepetin and kaempferol-3-O-galactoside after bromobenzene intoxication decreased serum glumate-pyruvate transaminase activity, although only the last flavonoid was able to significantly reduce hepatic lipid peroxidation products and to increase the reduced glutathione level. In contrast, morelloflavone increased bromobenzene toxicity.
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PMID:Influence of a series of natural flavonoids on free radical generating systems and oxidative stress. 797 32

1. The hepatic protective effects of the phenolic compounds 7,8-dihydroxyflavone, morin, silymarin, caffeic acid and chlorogenic acid on bromobenzene-induced toxicity in mice were studied. 2. Morin, caffeic acid and chlorogenic acid at an oral dose of 200 mg/kg failed to influence hepatotoxicity in vivo, while 7,8-dihydroxyflavone exhibited efficacy and potency higher than those of the reference compound silymarin. 3. 7,8-Dihydroxyflavone, an antioxidant and hepatoprotective agent in vitro, decreased serum glutamate-pyruvate transaminase levels (SGPT) in a dose-related manner, and at 200 mg/kg inhibited bromobenzene-induced glutathione depletion in liver.
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PMID:Effects of phenolic compounds on bromobenzene-mediated hepatotoxicity in mice. 849 95

Dimethyl sulfoxide (DMSO) can protect the liver from injury produced by a variety of hepatotoxicants when administered prior to or concomitant with the toxicants. This protective action has previously been attributed to DMSO-induced inhibition of bioactivation of the compounds to toxic intermediates. In these studies, the ability of DMSO to provide protection when administered 10 hr after a toxicant was evaluated in several animal models of xenobiotic-induced liver and kidney injury. In the guinea pig model of halothane-associated hepatotoxicity, male outbred Hartley guinea pigs received 2 ml/kg DMSO 10 hr after an inhalation exposure to 1.0% halothane, 40% O2 for 4 hr. DMSO decreased the extent of liver necrosis as indicated by a threefold decrease in plasma alanine aminotransferase activity 48 hr after exposure and a reduction in the incidence and extent of zone 3 necrosis. These results do not appear to be due to alterations in halothane biotransformation since DMSO administered at 10 hr after halothane had no affect on plasma concentrations of the halothane metabolite tritluoroacetic acid or covalent binding by reactive halothane biotransformation intermediates to hepatic protein. In addition, administration of the structurally analogous biotransformation inhibitor diallyl sulfide at 10 hr after halothane also had no affect on biotransformation or covalent binding but provided no protection from liver injury. Hepatic glutathione concentrations in the guinea pigs 24 hr after halothane exposure were also unaffected by late treatment with DMSO. Further studies in male Sprague-Dawley rats demonstrated the ability of DMSO to decrease the hepatic injury resulting from oral administration of 1.0 ml/kg chloroform or 0.5 ml/kg bromobenzene when administered 10 hr after either toxicant. The chloroform-treated rats also developed renal tubular necrosis with large increases in plasma creatinine and urea nitrogen, which were completely ameliorated by DMSO. Elucidating the mechanism(s) of this protective action of late DMSO administration should provide insight into the cascade of events that lead to liver and kidney injury from toxicants and, hopefully, therapeutic modalities for individuals suffering from acute, progressing, xenobiotic-induced hepatitis.
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PMID:Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. 900 50

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, chemicals whose hepatotoxicity is diminished by cotreatment with adrenergic antagonist drugs. In the case of cocaine, adrenergic antagonist cotreatment was capable of reducing serum alanine aminotransferase activities by approximately 50%. For bromobenzene, the protection afforded by adrenergic antagonist cotreatment was more profound, with minimal hepatic lesions resulting from doses of bromobenzene that otherwise produced lethal hepatic necrosis. For the chemicals in group II, experimental observations are consistent with a phenomenon in which adrenergic potentiation of toxicity is supplied by the hepatotoxicant itself. Both cocaine and bromobenzene, in hepatotoxic doses increase endogenous catecholamine levels. When the effects of the elevated catecholamines are removed with the appropriate adrenergic antagonist, much lower toxicity (presumably due only to the direct hepatotoxic effects of the drug or chemical) is obse
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PMID:Adrenergic modulation of hepatotoxicity. 918 24

Amphetamine has been shown previously to increase levels of the inducible 70-kDa heat shock protein (hsp70i) in mouse liver. In the present study, the hepatic concentrations of a variety of hsps in livers of mice pretreated with amphetamine (15 mg/kg, i.p.) were evaluated, and the time course of hsp induction was examined. Amphetamine treatment caused an acute rise in core body temperature to 40 degrees C for at least 1 hr and increased hsp25 and hsp70i levels, as measured by Western blotting, at 6, 24, 48, and 72 hr with no apparent induction of other hsps (hsp60, hsc70, or hsp90). A 72-hr amphetamine pretreatment lowered the hepatotoxicity of an acute dose of acetaminophen (350 mg/kg, i.p.) or bromobenzene (0.45 ml/kg, i.p.), but had no effect on the toxicity of carbon tetrachloride (0.04 ml/kg, i.p.) or cocaine (50 mg/kg, i.p.), as measured by serum alanine aminotransferase activity and histopathological analysis. No protection from acetaminophen or bromobenzene hepatotoxicity was observed when hepatotoxicant administration was delayed until hsp levels had returned to control values (144 hr after amphetamine pretreatment). Amphetamine pretreatment did not reduce in vivo covalent binding to proteins of radiolabeled [3H]acetaminophen, [14C]bromobenzene, [14C]carbon tetrachloride, or [3H]cocaine, indicating that the protective effects were not due to inhibition of reactive metabolite formation from these toxicants. These results suggest that elevated levels of hsp25 and hsp70i provide protection against acetaminophen and bromobenzene hepatotoxicity.
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PMID:Protection against hepatotoxicity by a single dose of amphetamine: the potential role of heat shock protein induction. 943 20


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