Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c14CoS/c14CoS mouse has a homozygous deletion of about 1.2 cM on chromosome 7 that includes the albino (c) locus. The untreated 14CoS/14CoS newborn has been reported to exhibit a marked transcriptional activation of the hepatic NAD(P)H:menadione oxidoreductase (Nmo-1; DT diaphorase; quinone reductase; azo dye reductase) gene, as well as elevated UDP glucuronosyl-transferase (UGT1*06) and glutathione transferase (GT1) activities, when compared with the cch/cch wild-type and the cch/c14CoS heterozygote. We show here that the newborn hepatic activities of seven enzymes that play a role in the oxidative stress response--NMO1, UGT1*06, GT1, copper-zinc superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase--are increased 1.5- to 25-fold in 14CoS/14CoS, as compared with ch/ch and ch/14CoS mice. The activities of four additional enzymes having no known association with the oxidative stress response--benzo[a]pyrene hydroxylase (CYP1A1, cytochrome P(1)450), acetanilide 4-hydroxylase (CYP1A2, cytochrome P(3)450), lactate dehydrogenase (LDH), and NADPH-cytochrome c reductase--are not significantly different among the three genotypes. These data suggest that there exists an "oxidative stress" response in the untreated 14CoS/14CoS newborn. We postulate that a chromosome 7 regulatory gene, which we have named Nmo-1n, might encode a trans-acting negative effector of the Nmo-1 gene, and genes corresponding to the other elevated enzymic activities described above. When both copies of Nmo-1n are deleted, as is the case in 14CoS/14CoS mice, a battery of genes involved in oxidative stress is released from negative control and becomes activated--despite the absence of any apparent oxidative insult by foreign chemicals.
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PMID:"Oxidative stress" response in liver of an untreated newborn mouse having a 1.2-centimorgan deletion on chromosome 7. 154 Jan 61

Dietary indole-3-carbinol inhibits carcinogenesis in rodents and trout. Several mechanisms of inhibition may exist. We reported previously that 3,3'-diindolylmethane, an in vivo derivative of indole-3-carbinol, is a potent noncompetitive inhibitor of trout cytochrome P450 (CYP) 1A-dependent ethoxyresorufin O-deethylase with Ki values in the low micromolar range. We now report a similar potent inhibition by 3,3'-diindolylmethane of rat and human CYP1A1, human CYP1A2, and rat CYP2B1 using various CYP-specific or preferential activity assays. 3,3'-Diindolylmethane also inhibited in vitro CYP-mediated metabolism of the ubiquitous food contaminant and potent hepatocarcinogen, aflatoxin B1. There was no inhibition of cytochrome c reductase. In addition, we found 3,3'-diindolylmethane to be a substrate for rat hepatic microsomal monooxygenase(s) and tentatively identified a monohydroxylated metabolite. These observations indicate that 3,3'-diindolylmethane can inhibit the catalytic activities of a range of CYP isoforms from lower and higher vertebrates in vitro. This broadly based inhibition of CYP-mediated activation of procarcinogens may be an indole-3-carbinol anticarcinogenic mechanism applicable to all species, including humans.
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PMID:The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450. 856 33

The influence of cell density and epidermal growth factor (EGF) on the expression and inducibility of cytochrome P450 (CYP) genes of the CYP3A and CYP1A families in adult human hepatocytes in primary culture has been evaluated. Only when cultured at subconfluence and in the presence of EGF did hepatocytes exhibit a proliferative response, assessed by measuring DNA synthesis and cyclin A accumulation. In the absence of EGF, the accumulation of CYP3A4 and CYP1A2 messenger RNAs (mRNAs) in response to their respective inducers (rifampicin and dioxin) was dramatically decreased in subconfluent culture with respect to confluent cultures. The presence of EGF only slightly decreased the accumulation of these mRNAs in both confluent and subconfluent cultures. The accumulation of CYP2D6 and CYP2E1 proteins, which are constitutively expressed in confluent cultures, and the production of fibrinogen and apolipoprotein (Apo) B100 exhibited similar behavior, while nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity was affected neither by cell density nor by EGF. In contrast, the accumulation of CYP1A1 mRNA in response to dioxin was similar in confluent and subconfluent cultures, irrespective of the presence of EGF. Interestingly, CYP3A7, a gene that is preferentially expressed in the fetal liver, was expressed constitutively neither in confluent nor in subconfluent cultures, irrespective of the presence of EGF. It is concluded that the loss of cell-cell contacts rather than the proliferative status of cells per se is responsible for the dramatic decrease in the expression of CYP genes, normally expressed in the adult human liver.
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PMID:Effect of cell density and epidermal growth factor on the inducible expression of CYP3A and CYP1A genes in human hepatocytes in primary culture. 914 35

The accumulation of basic drugs (cationic amphiphilic), such as beta-adrenergic antagonists, by pulmonary tissue is well known. Ring hydroxylation of nonselective beta-adrenergic blocking agent propranolol is mediated mainly by cytochrome P450 (CYP) 2D6 and N-desisopropylation by CYP1A2 in human and rat liver microsomes. In this study, the repeated administration of propranolol resulted in a marked inhibition of hepatic metabolism and an increase in its systemic availability, due to covalent binding of reactive metabolites (formed from 4-OH-propranolol) to liver microsomal P4502D enzymes. The absence of CYP1A2 and the presence of CYP2D in the lung suggest a different pulmonary metabolism of propranolol in comparison with those in the liver. In this study, we investigated its effects in vivo on some xenobiotic-metabolizing enzymes in rat type II pneumocytes (RTII) and rat alveolar macrophages (RAM). Twenty hours after the last multiple (7 days) oral administration, propranolol (100 mg/kg b.w.) decreased NADPH cytochrome c reductase activity and cytochrome P-450-dependent dealkylation of 7-benzyloxyresorufin (BROD) (CYP1A1, 2A1, 3A1) and 7-ethoxyresorufin (EROD) (CYP1A1) in RTII, while glutathione-S-transferase (GST), DT-diaphorase (QR), gamma-glutamyl transferase (gamma-GT) activities, intracellular reduced glutathione level and dealkylation of 7-pentoxyresorufin (PROD) (CYP2B1) were not changed. It was found that propranolol significantly increased NADPH cytochrome c reductase and BROD activities in RAM. The results suggest a different susceptibility of RTII and RAM to propranolol and its contrary effects on lung xenobiotic-metabolizing enzyme activities in both types of cells.
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PMID:Effects of propranolol on xenobiotic enzyme activities in rat type II pneumocytes and alveolar macrophages in vivo. 1473 27