Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous phytochemicals have been examined for their capacity to act as cancer chemopreventive agents. Dibenzoylmethane, a minor constituent of licorice and a compound structurally-related to curcumin, recently was identified as an effective inhibitor of chemically-induced rat mammary DNA-adduct formation and tumorigenesis (Carcinogenesis 19(1998)1039-1043). The present studies were conducted to examine the capacity of dibenzoylmethane to inhibit the formation of DNA adducts following exposure to benzo[a]pyrene (BP) and 1,6-dinitropyrene (1,6-DNP), and to stimulate the expression of glutathione-S-transferase (GST) and NAD(P)H-quinone reductase (QR) proteins in the human mammary epithelial cell line MCF-10F. In addition, the efficacy of dibenzoylmethane as an enzyme inducer and adduct inhibitor was compared with that of sulforaphane, a potent inducer of phase II detoxification enzymes and inhibitor of chemically-induced rat mammary tumorigenesis. Dibenzoylmethane at concentrations from 0.1 M to 2.0 microM inhibited BP-DNA adduct formation by 63 to 81%. Likewise, sulforaphane inhibited BP-DNA adduct formation by 68 to 80% over the same concentration range. DNA adduct formation following exposure to 1,6-DNP was significantly inhibited by 46 to 61% due to dibenzoylmethane treatment (0.1 to 2.0 microM) and 30 to 56% due to sulforaphane treatment at the same concentrations. The expression of QR and GSTP1-1 proteins were increased by 3 to 4-fold and 3 to 5-fold, respectively, for MCF-10F cells treated with sulforaphane (0.5-2.0 microM). Dibenzoylmethane treatment at the same concentrations did not induce GSTP1-1 expression and significantly stimulated QR expression only at the 2.0 microM concentration. These data indicate that human mammary epithelial MCF-10F cells can convert BP and 1,6-DNP to DNA-binding forms, and that DNA adduct formation can be inhibited by the phytochemicals dibenzoylmethane and sulforaphane. The inhibition of BP-DNA and 1, 6-DNP adduct formation by sulforaphane was associated with increases in QR and GST protein expression. The mechanisms underlying the capacity of dibenzoylmethane to inhibit BP-DNA and 1,6-DNP-DNA adduct formation could not be explained by changes in QR or GST expression and remain to be determined. Together these data suggest that dibenzoylmethane and sulforaphane warrant continued evaluation as breast cancer chemopreventive agents.
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PMID:Inhibition of benzo[a]pyrene- and 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells bydibenzoylmethane and sulforaphane. 1081 78

Amodiaquine (AQ), an antimalarial drug, widely prescribed in endemic areas of Africa and Asia, is used in combination with artesunate as recommended by the WHO. However, due to its idiosyncratic hepatotoxicity and agranulocytosis, the therapeutic use has been discontinued in most countries. Oxidative bioactivation to protein-reactive quinonimines (QIs) by hepatic cytochrome P450s and myeloperoxidase (MPO) have been suggested to be important mechanisms underlying AQ idiosyncratic toxicity. However, the inactivation of the reactive QIs by detoxifying enzymes such as human glutathione S-transferases (GSTs) and NAD(P)H:quinone oxidoreducatase 1 (NQO1) has not been characterized yet. In the present study, the activities of 15 recombinant human GSTs and NQO1 in the inactivation of reactive QIs of AQ and its pharmacological active metabolite, N-desethylamodiaquine (DEAQ) were investigated. The results showed that GSTP1-1, GSTA4-4, GSTM4-4, GSTM2-2 and GSTA2-2 (activity in decreasing order) were active isoforms in catalyzing GSH conjugation of reactive QIs of AQ and DEAQ. Additionally, NQO1 was shown to inactivate these QIs by reduction. Simulation of the variability of cytosolic GST-activity based on the hepatic GST contents from 22 liver donors, showed a large variation in cytosolic inactivation of QIs by GSH, especially at a reduced GSH-concentration. In conclusion, the present study demonstrates that a low hepatic expression of the active GSTs and NQO1 may increase the susceptibility of patients to AQ idiosyncratic hepatotoxicity.
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PMID:Human glutathione S-transferases- and NAD(P)H:quinone oxidoreductase 1-catalyzed inactivation of reactive quinoneimines of amodiaquine and N-desethylamodiaquine: Possible implications for susceptibility to amodiaquine-induced liver toxicity. 2847 57