Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N1-methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-l-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.
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PMID:Identification of enzymes responsible for nitrazepam metabolism and toxicity in human. 2860 3

Dantrolene is used for malignant hyperthermia during anesthesia, and it sometimes causes severe liver injury as a side effect. Dantrolene is metabolized to acetylaminodantrolene, which is formed via the reduction of dantrolene to aminodantrolene and subsequent acetylation. Formation of hydroxylamine during the metabolic process may be associated with liver injury. We identified the enzymes responsible for dantrolene metabolism in humans to elucidate the mechanism of liver injury. Dantrolene reductase activity was not detected in human liver microsomes, but it was detected in cytosol. Formation was increased in the presence of N1-methylnicotineamide, which is an electron donor to aldehyde oxidase 1 (AOX1). Potent inhibitors of AOX1 and a correlation study with a marker of AOX1 activity, namely phthalazine oxidase activity, in a panel of 28 human liver cytosol samples supported the role of AOX1 in dantrolene reduction. Acetylaminodantrolene formation from aminodantrolene was highly detected in recombinant N-acetyltransferase (NAT) 2 rather than NAT1. A glutathione trapping assay revealed the formation of hydroxylamine via an AOX1-dependent reduction of dantrolene but not via hydroxylation of aminodantrolene. In conclusion, we found that AOX1 and NAT2 were responsible for dantrolene metabolism in humans and that AOX1-dependent metabolism determines dantrolene-induced liver injury.
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PMID:Identification of enzymes responsible for dantrolene metabolism in the human liver: A clue to uncover the cause of liver injury. 2952 12

Human aldehyde oxidase 1 (AOX1) catalyzes the oxidation of various drugs and endogenous compounds. Recently, we found that AOX1 catalyzed the reduction of drugs such as nitrazepam and dantrolene. In this study, we aimed to clarify the substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs to obtain helpful information for drug development. We investigated whether 11 nitroaromatic drugs were reduced by AOX1 using recombinant AOX1 and human liver cytosol (HLC) in the presence of N1-methylnicotinamide, an electron donor to AOX1. We found that clonazepam, flunitrazepam, flutamide, nilutamide, nimesulide, and nimetazepam were substantially reduced by recombinant AOX1 and HLC, whereas azelnidipine, nifedipine, and nimodipine were slightly reduced and metronidazole and tolcapone were not reduced. Via structural analysis, we observed that nitroaromatic drugs reduced by AOX1 possessed a relatively electron-deficient nitro group. Since the addition of NADPH to human liver microsomes (HLM) did not increase the reductase activities of the drugs that were reduced by recombinant AOX1, it was determined that NADPH-dependent enzymes in microsomes, such as cytochrome P450, were not involved in this process. Inhibition studies using known AOX1 inhibitors supported the role of AOX1 in the reduction of drugs in HLC. In conclusion, this provides new information related to the substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs.
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PMID:Substrate selectivity of human aldehyde oxidase 1 in reduction of nitroaromatic drugs. 3036 27