methimazole and 1-benzylimidazole

methimazole has been researched along with 1-benzylimidazole* in 3 studies

Other Studies

3 other study(ies) available for methimazole and 1-benzylimidazole

ArticleYear
S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant.
    The Journal of pharmacology and experimental therapeutics, 2007, Volume: 321, Issue:3

    Previously, we have provided evidence that cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) are involved in the oxidation of S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) in rabbit liver microsomes to yield the reactive metabolite TCVC sulfoxide (TCVCS). Because TCVC is a known nephrotoxic metabolite of tetrachloroethylene, the nephrotoxic potential of TCVCS in rats and TCVCS formation in rat liver and kidney microsomes were investigated. At 5 mM TCVC, rat liver microsomes formed TCVCS at a rate nearly 5 times higher than the rate measured with rat kidney microsomes, whereas at 1 mM TCVC only the liver activity was detectable. TCVCS formation in liver and kidney microsomes was dependent upon the presence of NADPH and was inhibited by the addition of methimazole or 1-benzylimidazole, but not superoxide dismutase, catalase, KCN, or deferoxamine, consistent with the involvement of both FMOs and P450s. Rats given TCVCS at 230 micromol/kg i.p. exhibited acute tubular necrosis at 2 and 24 h after treatment, and they had elevated blood urea nitrogen levels at 24 h, whereas TCVC was a much less potent nephrotoxicant than TCVCS. Furthermore, pretreatment with aminooxyacetic acid enhanced TCVC toxicity. In addition, reduced nonprotein thiol concentrations in the kidney were decreased by nearly 50% 2 h after TCVCS treatment compared with saline-treated rats, whereas the equimolar dose of TCVC had no effect on kidney nonprotein thiol status. No significant lesions or changes in nonprotein thiol status were observed in liver with either TCVC or TCVCS. Collectively, the results suggest that TCVCS may play a role in TCVC-induced nephrotoxicity.

    Topics: Alanine Transaminase; Aminooxyacetic Acid; Animals; Aspartate Aminotransferases; Blood Glucose; Blood Urea Nitrogen; Cysteine; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; gamma-Glutamyltransferase; Glycosuria; Imidazoles; Kidney; Liver; Male; Methimazole; Microsomes; Microsomes, Liver; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds; Sulfoxides

2007
S-oxidation of S-methyl-esonarimod by flavin-containing monooxygenases in human liver microsomes.
    Xenobiotica; the fate of foreign compounds in biological systems, 2003, Volume: 33, Issue:12

    1. Studies using human liver microsomes and recombinant human cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) were performed to identify the enzymes responsible for the metabolism of S-methyl-esonarimod (M2), an active metabolite of esonarimod (KE-298, a novel antirheumatic drug). 2. S-oxidative activities of M2 significantly correlated with those of methyl p-tolyl sulfide, a specific substrate of FMOs, as tested using 10 different human liver microsomes (r(2) = 0.539, p<0.05). Thermal treatment of microsomes reduced the S-oxidative activity in the absence of the NADPH-generating system at 45 degrees C for 5 min. However, methimazole, a known competitive substrate of FMOs, was a weak inhibitor of the S-oxidation in liver microsomes. 3. Recombinant human FMO1 and FMO5 produced M3 in greater quantities than recombinant human FMO3. The S-oxidation of M2 by recombinant human FMO5 was not appreciably inhibited in the presence of methimazole. In contrast, methimazole was effective in suppressing the catalytic activity of recombinant human FMO1 and FMO3. 4. The apparent K(m) (K(m app)) for the S-oxidation of M2 in human recombinant FMO5 (2.71 microM) was similar to that obtained using human liver microsomes (2.43 microM). 5. The present results suggest that the S-oxidation of S-methyl esonarimod reflects FMO5 activity in the human liver because the recombinant FMO5 data match well with the human liver microsomal experiments.

    Topics: Cytochrome P-450 Enzyme System; Enzyme Activation; Humans; Imidazoles; Isoenzymes; Kinetics; Methimazole; Microsomes, Liver; NADP; Oxidation-Reduction; Oxygenases; Phenylpropionates; Recombinant Proteins; Thiourea

2003
A convenient method to discriminate between cytochrome P450 enzymes and flavin-containing monooxygenases in human liver microsomes.
    Archives of toxicology, 1996, Volume: 71, Issue:1-2

    Liver microsomes are a frequently used probe to investigate the phase I metabolism of xenobiotics in vitro. Structures containing nucleophilic hetero-atoms are possible substrates for cytochrome P450 enzymes (P450) and flavin-containing monooxygenases (FMO). Both enzymes are located in the endoplasmatic reticulum of hepatocytes and both need oxygen and NADPH as cofactors. The common method to distinguish between the two enzyme systems is to use the thermal inactivation of FMO and to inhibit P450 completely with carbon monoxide, N-octylamine or N-benzylimidazole. In the literature no indication could be found that the heat inactivation of FMO does not affect any of the human P450 enzymes or that the overall P450 inhibitors inhibit the different human P450 enzymes sufficiently and do not affect the FMO. The effect of N-benzylimidazole and heat inactivation was tested on specific activities of seven P450 enzymes in human liver microsomes, 1A2, 2A6, 2C9, 2C19, 2D6, 3A4/5, and 2E1, using methoxyresorufin O-demethylation, coumarin 7-hydroxylation, (S)-warfarin 4-hydroxylation, (S)-(+)-mephenytoin 4-hydroxylation, dextrometorphan O-demethylation, oxidation of denitronifedipine, and chlorzoxazone 6-hydroxylation respectively. The sulfoxidation of methimazole (MMI) was used as a specific probe for the determination of FMO activity. Methimazole sulfoxidation was compared with the well known assay for FMO metabolism, the formation of N,N-dimethylaniline (DMA) N-oxide, to be confirmed as an exclusively FMO mediated reaction. The participation of P450 and FMO in the sulfoxidation of four sulfur containing peptides, ametryne; terbutryne, prometryne and methiocarb was investigated using human liver microsomes. All four reactions were demonstrated to be catalysed predominantly by cytochrome P450.

    Topics: Aniline Compounds; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Herbicides; Hot Temperature; Humans; Imidazoles; Methimazole; Microsomes, Liver; Monoamine Oxidase; Oxidation-Reduction; Oxygenases; Triazines

1996