RESUMO
1. Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse. 2. The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ). 3. Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system. 4. Tissue viability, assessed through both structural and functional markers, was preserved throughout 12 h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p < 0.001) in the rates of appearance of (+) ABZSO. Conversely, in presence of MTZ, the rates of appearance of (-) ABZSO increased under both systems (p < 0.05). 5. Both culture systems were suitable for assessing the interaction between ABZ and MTZ. 6. Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug-drug interactions in the bovine species.
Assuntos
Interações Medicamentosas , Fígado/metabolismo , Administração Oral , Albendazol/análogos & derivados , Albendazol/metabolismo , Animais , Anti-Helmínticos/metabolismo , Bovinos , Metimazol/metabolismo , Microssomos Hepáticos/metabolismo , EstereoisomerismoRESUMO
It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T4 injection (20 µg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T4 showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T4 completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole.
Assuntos
Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Metimazol , Baço/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Animais , Amarelo de Eosina-(YS) , Hematoxilina , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/metabolismo , Hipotireoidismo/fisiopatologia , Hipotireoidismo/cirurgia , Masculino , Metimazol/efeitos adversos , Metimazol/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , TireoidectomiaRESUMO
Metabolic activities of several xenobiotic metabolizing enzymes were evaluated in both hepatic and enteric subcellular fractions obtained from Corriedale × Merino crossbreed rams by using a biochemical approach. Microsomes obtained from the different segments of sheep small intestinal mucosa displayed cytochrome P450 (CYP)-dependent N-demethylations but not O-deethylase activities apparently occurred. CYP-mediated N-demethylations neither decreased nor increased along the small intestinal mucosa. Percentages of activity for erythromycin N-demethylase in the small intestine were between 29% (duodenum) and 45% (ileum) from that measured in the liver, whereas those determined for triacetyl-oleandomycin N-demethylation ranged between 10% (duodenum) and 15% (jejunum) of the same hepatic activity. Conversely, metabolic rates for aminopyrine and chlorfeniramine N-demethylations in the gut mucosa ranged between 3% and 7% compared to their respective hepatic enzyme activities. Sheep enteric mucosa also displayed metabolic reactions typically mediated by flavin-containing monooxygenases (FMOs), carbonyl reductases (CBRs), carboxylesterases (CES), glutathione S-transferases (GSTs) and uridine diphosphoglucuronyltransferases (UGTs). The FMO-mediated sulfoxidation of methimazole was 2.6-fold higher (P < 0.01) in the ileal compared to the duodenal mucosa. Percentages of activity for the microsomal CBR-dependent biotransformation of menadione were between 12% (ileum) and 19% (duodenum-jejunum) of the total activity measured in the liver; metabolic rates measured in duodenum and jejunum were â¼1.7-fold higher (P < 0.05) than that observed in the ileum. The microsomal CES activity (using p-nitrophenyl acetate as substrate) was around twofold higher in duodenum (P < 0.05) and jejunum (P < 0.01) in comparison to the ileum. Cytosolic GST-dependent activities (toward 1-chloro, 2,4-dinitrobenzene) were similar in the mucosa of duodenum, jejunum and ileum. Microsomal UGT activities (toward 1-naphthol) in duodenum and jejunum were three- and fourfold higher, respectively, compared to that measured in the ileum. The small intestinal mucosa may play a critical defensive role due to its involvement in the detoxification of toxic compounds prior to absorption. In addition, gut metabolic reactions may contribute to the presystemic metabolism of orally administered drugs. These results are a further contribution to the understanding of the relevance of the extra-hepatic metabolism of xenobiotics in ruminant species.
Assuntos
Intestino Delgado/metabolismo , Ovinos/metabolismo , Animais , Duodeno/enzimologia , Duodeno/metabolismo , Íleo/enzimologia , Íleo/metabolismo , Mucosa Intestinal/enzimologia , Mucosa Intestinal/metabolismo , Intestino Delgado/enzimologia , Jejuno/enzimologia , Jejuno/metabolismo , Masculino , Metimazol/metabolismo , Microssomos/enzimologia , Microssomos/metabolismo , Microssomos Hepáticos/metabolismo , Oxirredução , Farmacocinética , Frações Subcelulares/enzimologia , Frações Subcelulares/metabolismo , Vitamina K 3/metabolismoRESUMO
Methimazole (MeimzH) is an anti-thyroid drug and the first choice for patients with Grave's disease. Two new copper(II) complexes of this drug: [Cu(MeimzH)(2)(NO(3))(2)]*0.5H(2)O and [Cu(MeimzH)(2)(H(2)O)(2)](NO(3))(2)*H(2)O were synthesized and characterized by elemental analysis, dissolution behavior, thermogravimetric analysis and UV-vis, diffuse reflectance, FTIR and EPR spectroscopies. As it is known that copper(II) cation can act as an inhibitor of alkaline phosphatase (ALP), the inhibitory effect of methimazole and its copper(II) complexes on ALP activity has also been investigated.