Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hexachlorobenzene (HCB) is a persistent environmental pollutant with toxic effects in man and rat. Reported adverse effects are hepatic porphyria, neurotoxicity, and adverse effects on the reproductive and immune system. To obtain more insight into HCB-induced mechanisms of toxicity, we studied gene expression levels using DNA microarrays. For 4 weeks, Brown Norway rats were fed a diet supplemented with 0, 150, or 450 mg HCB/kg. Spleen, mesenteric lymph nodes (MLN), thymus, blood, liver, and kidney were collected and analyzed using the Affymetrix rat RGU-34A GeneChip microarray. Most significant (p < 0.001) changes, compared to the control group, occurred in spleen, followed by liver, kidney, blood, and MLN, but only a few genes were affected in thymus. This was to be expected, as the thymus is not a target organ of HCB. Transcriptome profiles confirmed known effects of HCB such as stimulatory effects on the immune system and induction of enzymes involved in drug metabolism, porphyria, and the reproductive system. In line with previous histopathological findings were increased transcript levels of markers for granulocytes and macrophages. New findings include the upregulation of genes encoding proinflammatory cytokines, antioxidants, acute phase proteins, mast cell markers, complements, chemokines, and cell adhesion molecules. Generally, gene expression data provide evidence that HCB induces a systemic inflammatory response, accompanied by oxidative stress and an acute phase response. In conclusion, this study confirms previously observed (immuno)toxicological effects of HCB but also reveals several new and mechanistically relevant gene products. Thus, transcriptome profiles can be used as markers for several of the processes that occur after HCB exposure.
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PMID:Toxicogenomics of subchronic hexachlorobenzene exposure in Brown Norway rats. 1515 7

A new antiepileptic synaptic vesicle 2a (SV2a) ligand drug candidate was tested in 4-week oral toxicity studies in rat and dog. Brown pigment inclusions were found in the liver of high-dose dogs. The morphology of the deposits and the accompanying liver changes (increased plasma liver enzymes, increased total hepatic porphyrin level, decreased liver ferrochelatase activity, combined induction, and inactivation of cytochrome P-450 CYP2B11) suggested disruption of the heme biosynthetic cascade. None of these changes was seen in rat although this species was exposed to higher parent drug levels. Toxicokinetic analysis and in vitro metabolism assays in hepatocytes showed that dog is more prone to oxidize the drug candidate than rat. Mass spectrometry analysis of liver samples from treated dogs revealed an N-alkylprotoporphyrin adduct. The elucidation of its chemical structure suggested that the drug transforms into a reactive metabolite which is structurally related to a known reference porphyrogenic agent allylisopropylacetamide. That particular metabolite, primarily produced in dog but neither in rat nor in human, has the potential to alkylate the prosthetic heme of CYP. Overall, the data suggested that the drug candidate should not be porphyrogenic in human. This case study further exemplifies the species variability in the susceptibility to drug-induced porphyria.
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PMID:N-alkylprotoporphyrin formation and hepatic porphyria in dogs after administration of a new antiepileptic drug candidate: mechanism and species specificity. 2497 95