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)

The activities of certain drug metabolizing enzymes have been measured in liver and kidney slice preparations from domesticated birds. Aminopyrine demethylase activity was significantly lower in liver slices from the duck (Aylesbury X Pekin, Khaki-Campbell) than from the rat (Wistar), and in the Aylesbury X Pekin duck lower than in the turkey (Triple 6 FLX), chicken (Brown Leghorn, Rhode Island Red X Light Sussex) and goose (Emden X Doulouse). The microsomal cytochrome P-450 was lower in duck liver (Aylesbury X Pekin) than in rat liver, and the aniline hydroxylase and aminopyrine demethylase activities in a 10,000 g supernatant fraction of liver were lower in duck preparations (Aylesbury X Pekin, Khaki-Campbell) than rat preparations. These observations suggest that the duck is likely to be susceptible to drugs which are metabolized by the cytochrome P-450 containing mono-oxygenases. UDP-Glucuronyl transferase activity was not detectable in liver and kidney slices from two mature geese. This observation was not the outcome of a deficiency of UDP-glucuronic acid, rapid breakdown of glucuronide by beta-glucuronidase or the presence of a substance inhibitory to UDP-glucuronyl transferase. Liver slices from geese, ducks (Aylesbury X Pekin) and chickens contained low UDP-glucuronyl transferase and high sulphate conjugation enzyme activities, whereas the reverse was found in Khaki-Campbell ducks. The activities of UDP-glucuronyl transferase and the sulphate conjugation enzymes were both relatively high in liver slices from the turkey and rat. The kidney contained lower enzyme activities than the liver except in the duck (Aylesbury X Pekin), in which low activities of aminopyrine demethylase and UDP-glucuronyl transferase were present in slices of both organs. In liver slices from chickens and geese the activities of aminopyrine demethylase and the sulphate conjugation enzymes were similar in mature and immature birds, and the activity of UDP-glucuronyl transferase was considerably higher in chicks and goslings than in mature birds of the same species. In the chick the activities of aminopyrine demethylase, UDP-glucuronyl transferase and the sulphate conjugation enzymes were higher in the duodenum than the remainder of the alimentary tract. The activities of these enzymes in pieces of duodenum were as high as those in slices of liver. The inclusion of sulphate in the incubation medium produced a significant increase in the synthesis of p-nitrophenyl sulphate in liver slices and not kidney slices except those from the duck. The kidney slices seemed to produce sufficient sulphate for the reaction of the sulphate conjugation enzymes to proceed at the maximum rate, but the liver slices did not do so.
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PMID:Activities of mixed function oxidases, UDP-glucuronyl transferase and sulphate conjugation enzymes in galliformes and anseriformes. 81 57

The effect of age and gender on the in vitro biotransformation of 2-methylpropene, an alkene metabolized to 2-methyl-1,2-epoxypropane, was studied. The epoxide concentration and the epoxide metabolizing enzymatic activities were investigated in male and female Brown Norway rats of different ages. Liver tissue of senescent rats was exposed to smaller 2-methyl-1,2-epoxypropane concentrations than that of young animals, although changes during ageing were rather modest. With advancing age a feminization of male glutathione S-transferase and cytosolic epoxide hydrolase activities was found, as well as a significant decline of the female microsomal epoxide hydrolase activity and an increase of the cytochrome P-450 content in the oldest female rats.
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PMID:Age- and gender-related changes in the hepatic metabolism of 2-methylpropene and relationship to epoxide metabolizing enzymes. 793 1

Raising extracellular Ca2+ (Ca2+o) stimulating the Ca(2+)-sensing receptor (CaR) decreased the activity of the apical 70-pS K+ channel via a cytochrome P-450-dependent mechanism in the thick ascending limb (TAL) of the rat kidney [W. H. Wang, M. Lu, and S. C. Hebert. Am. J. Physiol. 270 (Cell Physiol. 39): C103-C111, 1996]. We have now used the patch-clamp technique and fluorescent dyes to investigate the signaling mechanism by which this effect is produced. Addition of 500 microM gadolinium (Gd3+), an agent which has been shown to activate the CaR (E. M. Brown, G. Gamba, D. Riccardi, M. Lombardi, R. Butters, O. Kifor, A. Sun, M. A. Hediger, J. Lytton, and S. C. Hebert. Nature 366: 575-580, 1993), mimics the inhibitory effect of raising Ca2+o from 1.1 to 5 mM on channel activity. Effects of the high Ca2+o and Gd3+ were abolished by blockade of phospholipase A2 (PLA2) but not by inhibition of phospholipase C (PLC). Raising Ca2+o also increased 20-hydroxyeicosatetraenoic acid production significantly. To investigate the effect of stimulation of the CaR on intracellular Ca2+ (Ca2+i), we used the acetoxymethyl ester of fura 2 to monitor the Ca2+i. Raising Ca2+o from 1.1 to 5 mM increased the Ca2+i significantly from 50 to 150 nM. However, addition of thapsigargin failed to abolish the effect of 5 mM Ca2+o on Ca2+i. Also, application of Gd3+ only slightly increased the Ca2+i, suggesting that elevation of the Ca2+i by high Ca2+o was the result of an influx of Ca2+ rather than enhanced Ca2+ release from Ca2+ stores. That the increase in Ca2+ influx is not mainly responsible for the effect of stimulating the CaR on channel activity is further supported by experiments in which 500 microM Gd3+ inhibited the K+ channel in cell-attached patches in a Ca(2+)-free bath. Furthermore, addition of 500 microM Gd3+ or 5 mM Ca2+o decreased intracellular Na+ measured with fluorescent sodium indicator, suggesting inhibition of Na+ transport. We conclude that PLA2 is involved in the stimulation of the CaR-induced inhibition of apical K+ channels in the TAL.
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PMID:Phospholipase A2 is involved in mediating the effect of extracellular Ca2+ on apical K+ channels in rat TAL. 932 15

This study sought to identify the mechanisms of vascular relaxation that are rescued in middle cerebral arteries (MCA) of SS.13BN consomic rats by substituting chromosome 13 containing the renin gene from Brown Norway (BN) rats into the Dahl salt-sensitive (SS) genetic background. Isolated MCA from SS rats exhibited an indomethacin-sensitive constriction in response to acetylcholine (ACh) and hypoxia. ACh-induced dilation was NO dependent and hypoxic dilations were cyclooxygenase (COX) dependent in BN and SS.13BN rats. In SS rats, hypoxic dilation was restored by indomethacin and abolished by inhibiting cytochrome P-450 epoxygenases, suggesting a role for epoxyeicosatrienoic acids. MCA from SS and SS.13BN rats constricted and MCA from BN rats dilated in response to the stable prostacyclin analog iloprost. MCA from SS.13BN and BN rats (but not SS rats) dilated in response to the prostaglandin E2 receptor agonist butaprost. Hypoxia increased prostacyclin release in cerebral arteries from all the strains, whereas thromboxane A2 production was reduced in BN rat vessels only. These data suggest that SS rats may be less sensitive to vasodilator prostaglandins and that normalization of renin-angiotensin system regulation causes a switch from production of COX-derived vasoconstrictor metabolites (in SS rats) toward NO-dependent relaxation in response to ACh- and prostaglandin-dependent dilation in response to hypoxia in SS.13(BN) rats.
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PMID:Restoration of normal vascular relaxation mechanisms in cerebral arteries by chromosomal substitution in consomic SS.13BN rats. 1577 73

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