Benzydamine as a useful substrate of hepatic flavin‐containing monooxygenase activity in veterinary species

Capolongo, Francesca; Santi, Annalisa; Anfossi, P.; Montesissa, Clara

doi:10.1111/j.1365-2885.2009.01145.x

Cited by 15 publications

(19 citation statements)

References 28 publications

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“…The relative contribution of CYPs and FMO3 in the metabolism of THT was studied by heat-inactivation of FMO3 in some incubations [ 16 ] and, in other incubations, CYP enzymes in HLM were inactivated [ 17 ] by carbon monoxide (AGA Gas, Enköping, Sweden) bubbling.…”

Section: Methodsmentioning

confidence: 99%

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway

El-Serafi¹,

Terelius²,

Abedi‐Valugerdi³

et al. 2017

PLoS ONE

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Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood. In the present study, we performed in vitro and in vivo investigations to elucidate the involvement of flavin-containing monooxygenase-3 (FMO3) and cytochrome P450 enzymes (CYPs) in Bu metabolic pathway. Rapid clearance of THT was observed when incubated with human liver microsomes. Furthermore, among different recombinant microsomal enzymes, the highest intrinsic clearance for THT was obtained via FMO3 followed by several CYPs including 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4. In Bu- or THT-treated mice, inhibition of FMO3 by phenylthiourea significantly suppressed the clearance of both Bu and THT. Moreover, the simultaneous administration of a high dose of THT (200μmol/kg) to Bu-treated mice reduced the clearance of Bu. Consistently, in patients undergoing HSCT, repeated administration of Bu resulted in a significant up-regulation of FMO3 and glutathione-S-transfrase -1 (GSTA1) genes. Finally, in a Bu-treated patient, additional treatment with voriconazole (an antimycotic drug known as an FMO3-substrate) significantly altered the Bu clearance. In conclusion, we demonstrate for the first time that FMO3 along with CYPs contribute a major part in busulphan metabolic pathway and certainly can affect its kinetics. The present results have high clinical impact. Furthermore, these findings might be important for reducing the treatment-related toxicity of Bu, through avoiding interaction with other concomitant used drugs during conditioning and hence improving the clinical outcomes of HSCT.

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Section: Methodsmentioning

confidence: 99%

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway

El-Serafi¹,

Terelius²,

Abedi‐Valugerdi³

et al. 2017

PLoS ONE

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“…In fact, MMI is used clinically as an anti‐thyroid drug as it inhibits thyroid peroxidase . It is S‐oxygenated by FMOs and it acts as an alternate substrate inhibitor .…”

Section: Resultsmentioning

confidence: 99%

“…Most of the apparent FMO inhibition is due to alternate substrate competitive inhibition where a good nucleophile competes with the drug for FMO oxygenation. The most commonly used alternative substrate inhibitor of FMOs is methimazole (MMI) , whereas thiourea , trimethylamine, N , N ‐dimethylaniline and chlorpromazine have also been used. All these features of FMOs support an important role of FMOs in human drug metabolism and highlight the need for further studies.…”

Section: Introductionmentioning

confidence: 99%

Development of a CD‐MEKC method for investigating the metabolism of tamoxifen by flavin‐containing monooxygenases and the inhibitory effects of methimazole, nicotine and DMXAA

et al. 2012

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A selective and low-cost CD-MEKC method under acidic conditions was developed for investigating the N-oxygenation of tamoxifen (TAM) by flavin-containing monooxygenases (FMOs). The inhibitory effects of methimazole (MMI), nicotine and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on the given FMO reaction were also evaluated; 100 mM phosphate buffer (pH 8.6) was used for performing the enzymatic reaction and the separation of TAM and its metabolite tamoxifen N-oxide (TNO) was obtained with a BGE consisting of 100 mM phosphoric acid solution adjusted to pH 2.5 with triethanolamine containing 50 mM sodium taurodeoxycholate, 20 mM carboxymethyl β-CD and 20% ACN. The proposed method was applied for the kinetics study of FMO1 using TAM as a substrate probe. A Michaelis-Menten constant (K(m)) of 164.1 μM was estimated from the corrected peak area of the product, TNO. The calculated value of the maximum reaction velocity (V(max)) was 3.61 μmol/min/μmol FMO1; 50% inhibitory concentration and inhibition constant (K(i)) of MMI, the most common alternate substrate FMO inhibitor, were evaluated and the inhibitory effects of two other important FMO substrates, nicotine and DMXAA, a novel anti-tumour agent, were investigated.

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“…Some of these studies represented the starting point for the evaluation of cattle DME activities. However, it should be underlined that some enzyme-substrate kinetic studies have already been published for bovines [ 97 , 104 , 105 , 106 , 107 , 108 ].…”

Section: Discussionmentioning

confidence: 99%

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Cantiello

Carletti

Giantin

et al. 2022

IJMS

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In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB’s post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs.

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Benzydamine as a useful substrate of hepatic flavin‐containing monooxygenase activity in veterinary species

Cited by 15 publications

References 28 publications

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway

Development of a CD‐MEKC method for investigating the metabolism of tamoxifen by flavin‐containing monooxygenases and the inhibitory effects of methimazole, nicotine and DMXAA

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

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