Alterations in mouse liver monooxygenases by benzothiadiazoles

“…After centrifugation a 1 ml aliquot of the supernatant was taken out and reaction with Nash reagent (contained in 100 ml: ammonium acetate 15.4 g, acetic acid 0.29 ml, acetylacetone 0.2 ml) was performed for 30 minutes in 60 8C. Absorbance of samples was measured at 415 nm (16).…”

Section: Enzyme Assaysmentioning

confidence: 99%

Effect of Sesquiterpene Lactones on Antioxidant Enzymes and Some Drug-Metabolizing Enzymes in Rat Liver and Kidney

Jodynis‐Liebert¹,

Murias²,

Bloszyk³

2000

Planta Med

100

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Previously we have reported that several sesquiterpene lactones isolated from Helenium aromaticum and Telekia speciosa showed pro-oxidative properties and caused glutathione level depletion in rat liver in vivo. In the present study we examined the in vivo effect of these lactones on antioxidant enzyme systems and some drug metabolizing enzymes in the liver and the kidney of rats. We found that the majority of the compounds increased the hepatic activity of glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT), but superoxide dismutase (SOD) activity was distinctly lowered by five lactones. A few of the compounds tested caused a decrease in the hepatic cytochrome P450 content and reduced the activity of NADPH-cytochrome P450 reductase, aminopyrine demethylase, aniline hydroxylase and glutathione-S-transferase. Results for the kidney showed fewer changes in activities of both classes of enzymes when compared to the liver. Not all lactones affected the enzymes under test, the most active were: linifolin, helenalin, mexicanin 1 and telekin. 6 alpha-Hydroxy-2,3-dihydroaromaticin behaved differently towards monooxygenases since it induced the activity of aminopyrine demethylase and aniline hydroxylase.

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“…Thus, 1,2,4‐thiadiazoles can be used to trap cysteine residues by mixed disulfide formulation [28]. Alternatively, 1,2,3‐benzothiazoles have been shown to inhibit cytochrome P450 metabolites by interference with electron transport within the catalytic cycle of cytochrome P450 [29]. Details of the potential binding and electron transfer events that may account for the uncompetitive inhibition of MetS by nitrobenzothiadiazole 2b are the subject of continuing investigation in this laboratory.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of cobalamin‐dependent methionine synthase by substituted benzo‐fused heterocycles

et al. 2006

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The cobalamin–dependent cytosolic enzyme, methionine synthase (EC.2.1.1.13), catalyzes the remethylation of homocysteine to methionine using 5‐methyltetrahydrofolate as the methyl donor. The products of this remethylation – methionine and tetrahydrofolate – participate in the active methionine and folate pathways. Impaired methionine synthase activity has been implicated in the pathogenesis of anaemias, cancer and neurological disorders. Although the need for potent and specific inhibitors of methionine synthase has been recognized, there is a lack of such agents. In this study, we designed, synthesized and evaluated the inhibitory activity of a series of substituted benzimidazoles and small benzothiadiazoles. Kinetic analysis revealed that the benzimidazoles act as competitive inhibitors of the rat liver methionine synthase, whilst the most active benzothiadiazole (IC50 = 80 µm) exhibited characteristics of uncompetitive inhibition. A model of the methyltetrahydrofolate‐binding site of the rat liver methionine synthase was constructed; docking experiments were designed to elucidate, in greater detail, the binding mode and reveal structural requirements for the design of inhibitors of methionine synthase. Our results indicate that the potency of the tested compounds is related to a planar region of the inhibitor that can be positioned in the centre of the active site, the presence of a nitro functional group and two or three probable hydrogen‐bonding interactions.

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Alterations in mouse liver monooxygenases by benzothiadiazoles

Cited by 10 publications

References 27 publications

Protective effect of Aquilegia vulgaris (L.) on APAP-induced oxidative stress in rats

Protective effect of Aquilegia vulgaris (L.) on APAP-induced oxidative stress in rats

Effect of Sesquiterpene Lactones on Antioxidant Enzymes and Some Drug-Metabolizing Enzymes in Rat Liver and Kidney

Inhibition of cobalamin‐dependent methionine synthase by substituted benzo‐fused heterocycles

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