Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have indicated that mice which differ in their acute susceptibility to responses mediated by the Ah receptor have a pattern of suppression of the antibody response which is consistent with a role by the putative dioxin receptor. The objective of the present investigation was to compare the TCDD-induced suppression of the antibody response following acute and subchronic exposures in B6C3F1 mice, an Ah-high-responder strain, and DBA/2 mice, an Ah-low-responder strain. Results of our initial studies demonstrate that suppression of humoral immunity can be enhanced in DBA/2 mice approximately 10-fold following subchronic versus acute exposures to the same cumulative doses of TCDD. This change in suppression of the antibody response in DBA/2 mice was not accompanied by significant changes in liver weight (hepatomegaly), as was observed in the B6C3F1 strain when exposed under comparable conditions. In contrast, effects on thymus weight (involution) were enhanced in the DBA/2 mice following subchronic exposure and demonstrated a higher degree of atrophy than was seen in the B6C3F1 strain (68 versus 56% decrease in thymic weight at the 42 micrograms/kg cumulative dose). These findings suggest that multiple mechanisms may be operating to suppress humoral immunity in vivo and that the conditions of exposure can alter the toxic effects of TCDD in the DBA/2, Ah-low responsive, mouse strain.
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PMID:Enhanced suppression of humoral immunity in DBA/2 mice following subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 131 Jan 64

The organic phase of a leachate (OPL) from the Love Canal chemical dump site contains more than 100 organic compounds including 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). The teratogenic potential of OPL was determined in two inbred and one hybrid mouse strain which differ in their sensitivity to aromatic hydrocarbon (Ah) receptor-mediated toxicity. OPL was orally administered in corn oil on Days 6-15 of gestation to C57BL/6J mice (Ahb/Ahb) at doses of 0, 0.1, 0.3, 0.5, and 0.7 g kg-1 day-1 and to DBA/2J (Ahd/Ahd) females, which were mated with either DBA/2J or C57BL/6J males, at 0, 0.5, 1, and 2.0 g kg-1 day-1. In C57BL/6J mice, which express a high-affinity Ah receptor that avidly binds TCDD, the ED50's of OPL for cleft palate and hydronephrosis were 0.44 and 0.11 g OPL kg-1 day-1, respectively. Maternal mortality was 5% at the highest dose. In DBA/2J fetuses, which express a low-affinity receptor, neither treatment-related cleft palate nor hydronephrosis was induced by dose levels that caused 36% maternal mortality. In hybrid D2B6F1 fetuses, the incidence of cleft palate reached only 8% at 2 g OPL kg-1 day-1 but the ED50 for hydronephrosis was 0.76 g OPL kg-1 day-1. TCDD was similarly administered to pregnant C57BL/6J mice at 0, 0.5, 1, 2, and 4 micrograms kg-1 day-1 and to DBA/2J mice at 0, 0.5, 2, 4, and 8 micrograms kg-1 day-1. In C57BL/6J fetuses, the ED50's for cleft palate and hydronephrosis were 4.6 and 0.73 microgram TCDD kg-1 day-1, respectively. In DBA/2J fetuses the ED50's for cleft palate and hydronephrosis were 15.0 and 6.4 micrograms TCDD kg-1 day-1, respectively. Both the OPL and TCDD caused maternal hepatomegaly and thymic atrophy in all strains, but increased only C57BL/6J fetal weights. OPL decreased the number of fetuses per C57BL/6J dam at the two highest doses but there were no other reproductive effects in any of the groups. It was concluded that the OPL is teratogenic and that hydronephrosis is a sensitive measure of TCDD toxicity in a complex organic mixture. Based on the ED50's of OPL- and TCDD-induced cleft palate and hydronephrosis in the C57BL/6J strain, the OPL had TCDD equivalence of 6.6 and 10.5 ppm, respectively. These values compare closely with the chemical analysis of 3 ppm.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a complex environmental mixture from the love canal. 276 49

The influence of 1-benzylimidazole on the activities of hepatic monooxygenases cytochromes P-450 dependent, epoxide hydrolases and UDP-glucuronosyltransferases was investigated in male Wistar rats. Several doses (25, 75 and 100 mg/kg/day) were administered gastrically during 5 days in order to evaluate the dose-related induction. The treatment caused a dose-dependent hepatomegaly. 1-Benzylimidazole decreased the plasma level in triglycerides by 60-70%; by contrast the cholesterol content was not changed during the time course of the experiment. Lauric acid hydroxylase, benzphentamine N-demethylase, 7-ethoxyresorufin O-deethylase, 7-ethoxycoumarin O-deethylase activities were increased 3.5-, 4-, 13- and 46-fold, respectively with the highest dose. By immunoblotting, an enhancement in the protein bands corresponding to cytochromes P-450c and P-450b could be simultaneously observed, whatever the dose administered, thus suggesting an induction process. However, 1-benzylimidazole failed to bind with high affinity to the cytosolic Ah receptor. On the other hand, measurement of the activity of the microsomal epoxide hydrolase with benzo(a)pyrene-4,5-oxide as substrate and quantitation of the enzyme protein by immunoassay revealed that the increase in the activity after treatment with the compound was the result of enzyme activation only. By contrast, cytosolic epoxide hydrolase was not affected by 1-benzylimidazole. This compound also stimulated three distinct forms of UDP-glucuronosyltransferase. The activities towards 4-methylumbelliferone, 1-naphthol, morphine or a monoterpenoid alcohol, nopol, supported by two different isozymes were significantly increased only with the highest dose; meanwhile bilirubin glucuronidation was 2-fold enhanced, whatever the dose used. These observations emphasize the variety of the effects of 1-benzylimidazole on drug-metabolizing enzymes.
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PMID:Effect of 1-benzylimidazole on cytochromes P-450 induction and on the activities of epoxide hydrolases and UDP-glucuronosyltransferases in rat liver. 284 Sep 13

Diets containing coho salmon (Oncorhynchus kisutch Walbaum) from the Pacific Ocean or from Lakes Erie, Michigan, and Ontario [containing a gradation from low to high of halogenated aromatic hydrocarbons, (HAHs)] were fed to C57B1/6 and DBA/2 mice. Following a 4-month dietary exposure to Lake Ontario salmon, both strains of mice demonstrated hepatomegaly. The ethoxyresorufin-O-deethylase (ERR) enzyme levels were elevated in livers of C57B1/6 mice fed diets of salmon from all of the Great Lakes studied, with exceptionally high levels detected in C57B1/6 mice fed Lake Ontario salmon. Induction of ERR enzyme levels was detected in DBA/2 mice only following dietary exposure to Lake Ontario salmon. Serum levels of L-thyroxine (T4) and triiodo-L-thryonine (T3) were suppressed in C57B1/6 mice following consumption of Lake Ontario coho salmon, but T3 and T4 levels remained unchanged in DBA/2 mice. In general, pathobiological effects correlated with both dietary HAH exposure level and Ah receptor status.
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PMID:Toxic effects in C57B1/6 and DBA/2 mice following consumption of halogenated aromatic hydrocarbon-contaminated Great Lakes coho salmon (Oncorhynchus kisutch Walbaum). 369 36

There is increasing need to understand the toxicity of complex environmental mixtures. The organic phase of a leachate (OPL) from the Love Canal chemical dump site is a complex mixture that contains over 100 organic compounds, including 0.74 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mice congenic at the Ah locus were used to evaluate several toxic effects of the OPL, including immune function and hepatic enzyme induction. OPL toxicity was compared with that of pure TCDD in both C57BL/6J Ahb/b and congenic C57BL/6 Ahd/d (B6.D2) mice. Mice were given single oral doses of up to 2 g OPL/kg or 100 micrograms TCDD/kg, immunized, and evaluated after 7 days. The TCDD equivalent of the OPL was determined to be 3.9 and 5.0 ppm in C57BL/6J and B6.D2 mice, respectively. This is six times the TCDD content. The Ah phenotype-dependent response ratio was calculated by dividing the dose required to cause an effect in the B6.D2 strain by the dose causing the same effect in the C57BL/6J strain. Ratios based on both ED50s and the lowest observed adverse effect levels were used to determine whether each adverse effect was Ah phenotype-dependent, the extent to which TCDD contributed to the effect, whether there were interactive effects between the AhR ligands and nonligands and if they were additive, antagonistic, or synergistic, and whether the response was predictable based on the known chemical composition of the mixture. It was concluded that the non-TCDD component potentiated TCDD immune suppression, and possibly thymic atrophy, through AhR mechanisms. In contrast, this analysis indicated that the non-TCDD component of the OPL antagonized the ability of the TCDD component to induce hepatic AHH activity whereas OPL hepatomegaly was caused primarily by the non-TCDD component of the OPL. This study demonstrates that the toxicity of mixtures containing TCDD may not be accurately predicted based on the TCDD content alone and that this approach could be useful in the toxicologic assessment and management of environmental contamination.
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PMID:Potentiation and antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin effects in a complex environmental mixture. 848 Mar 32

The Ah receptor (AHR) mediates the metabolic adaptation to a number of planar aromatic chemicals. Essential steps in this adaptive mechanism include AHR binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the Ah receptor nuclear translocator, and binding of this heterodimeric transcription factor to dioxin-responsive elements (DREs) upstream of promoters that regulate the expression of genes involved in xenobiotic metabolism. The AHR is also involved in other aspects of mammalian biology, such as the toxicity of molecules like 2,3,7,8-tetrachlorodibenzo-p-dioxin as well as regulation of normal liver development. In an effort to test whether these additional AHR-mediated processes require a nuclear event, such as DRE binding, we used homologous recombination to generate mice with a mutation in the AHR nuclear localization/DRE binding domain. These Ahr(nls) mice were found to be resistant to all 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxic responses that we examined, including hepatomegaly, thymic involution, and cleft palate formation. Moreover, aberrations in liver development observed in these mice were identical to that observed in mice harboring a null allele at the Ahr locus. Taken in sum, these data support a model where most, if not all, of AHR-regulated biology requires nuclear localization.
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PMID:Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor. 1262 Oct 46

Flutamide (FLU), an oral, nonsteroidal antiandrogen drug used in the treatment of prostate cancer, is associated with idiosyncratic hepatotoxicity that sometimes causes severe liver damage, including cholestasis, jaundice, and liver necrosis. To understand the mechanism of toxicity, a combination of aryl hydrocarbon receptor (Ahr)-deficient (Ahr-/-) mice, primary hepatocytes, luciferase reporter gene assays, in silico ligand docking and ultra-performance chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics was used. A significant increase of liver weights, and liver and serum bile acid levels was observed after FLU treatment, indicating hepatomegaly and disrupted bile acid homeostasis. Expression of the AhR gene battery was markedly increased in livers of wild-type mice Ahr+/+ treated with FLU, while no change was noted in Ahr-/- mice. Messenger RNAs encoded by AhR target genes were induced in primary mouse hepatocytes cultured with FLU, which confirmed the in vivo results. Ligand-docking analysis further predicted that FLU is an AhR agonist ligand which was confirmed by luciferase reporter gene assays. Multivariate data analysis showed that bile acids were responsible for the separation of vehicle- and FLU-treated Ahr+/+ mice, while there was no separation in Ahr-/- mice. Expression of mRNA encoding the bile acid transporter ABCC4 was increased and farnesoid X receptor signaling was inhibited in the livers of Ahr+/+ mice, but not in Ahr-/- mice treated with FLU, in agreement with the observed downstream metabolic alterations. These findings provide new insights into the mechanism of liver injury caused by FLU treatment involving activation of AhR and the alterations of bile acid homeostasis, which could guide clinical application.
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PMID:The antiandrogen flutamide is a novel aryl hydrocarbon receptor ligand that disrupts bile acid homeostasis in mice through induction of Abcc4. 2756 25