Estudo do papel das células de kupffer na modulação dos citocromos P450 hepáticos por estímulos inflamatórios

É conhecido que processos inflamatórios podem modular a expressão e atividade deenzimas CYPs. Não é claro, entretanto, o modo pelo qual estímulos inflamatórios regulam aexpressão dessas enzimas. Neste trabalho investigamos a hipótese de que as células deKupffer do fígado exerceriam um papel na modulação dos CYPs hepáticos em resposta àinflamação exacerbada ou sepse. O cloreto de gadolínio, é um inibidor seletivo das células deKupffer, conhecido por atenuar o quadro de inflamação exacerbada, quandoadministradopreviamente ao estímulo inflamatório, em diferentes modelos animais. Algunsautores sugeriram que as células de Kupffer atuariam como intermediários na modulação daatividade de CYPs hepáticos desencadeada por estímulos inflamatórios. Há estudos quesugerem que a diminuição da população das células de Kupfferatenua ou elimina a regulaçãodas CYPs hepáticas por estímulos inflamatórios.Além disso, estudos em culturas dehepatócitos in vitro, na ausência de células de Kupffer, tem constatado a regulação negativa daexpressão de CYPs hepáticas após estimulação com LPS. Nessa linha, o objetivo destepresente trabalho é investigar o papel das células de Kupffer na regulação da atividade deenzimas hepáticas de biotransformação de xenobióticos (CYPs) após estimulação inflamatóriacom LPS. Para isso, os níveis séricos de transaminases, e a histopatologia foram empregadospara avaliar o efeito do tratamento com diferentes doses de GdCl3sobre o tecido hepático.Noexperimento principal para investigar o papel das células de Kupffer, os ratos foram alocadosao acaso em quatro grupos. Foram quantificadosmarcadores bioquímicos no soro dos animaispara evidenciar danos ao tecido hepático causados pelos tratamentos e realizado o examehistopatológico...

It is known that inflammatory processes may modulate the expression and activity ofCYP enzymes. The mode by which inflammatory stimuli regulate CYP expression andactivity, however, remains unclear. Kupffer cells are resident macrophages in the liver andthus play an important role in a systemic inflammatory process or in sepsis. Gadoliniumchloride (GdCl3) has been reported to selectively kill an/or inhibit the activity of Kupffercells. Along this line, it has also been described that Gd decreases exacerbated inflammatoryresponses when it is administered prior to inflammatory stimuli in various animal models.Therole of Kupffer cells in the modulation of CYPs activity triggered by inflammatory stimuli,however, is not entirely clear in the literature. There are studies suggesting that a reduction inthe population of Kupffer cells attenuates the down-regulation of hepatic CYPs induced byinflammatory stimuli. However, GdCl3 was also described to decrease liver CYP activityirrespective of whether it depletes or not Kupffer cells. Moreover, in vitro studies showed thatLPS down-regulates the expression of CYP forms in hepatocyte cell lines in culture (in theabsence of Kupffer cells). To investigate whether Kupffer cells play a role in the regulation ofthe activity of liver xenobiotic biotransformation enzymes (CYPs) by inflammatorystimulation with LPS. The activity of transaminases in the blood serum (a marker for liverinjury) was determined and liver histopathology was evaluated in female Wistar rats. In a setof preliminary tests, rats were treated with different doses of GdCl3 or with LPS for selectingdoses and euthanasia time in the main experiment. In the main study experimental groups.Treatment associated liver injury was evaluated by levels of transaminases and alkalinephosphatase in the blood serum and by liver histopathology examination...

Cytochrome P450 2E1 activity in a Korean population

Cytochrome P450 2E1 (CYP2E1) is involved in the toxicity and carcinogenicity of a number of solvents and xenobiotics. Like the various types of oxidation pharmacogenetics, the activity of the enzyme shows a discernible interindividual and interethnic variation. However, no pharmacogenetic information on CYP2E1 polymorphism has been available from a Korean population. The aim of this study was to explore the pharmacogenetics of CYP2E1 polymorphism in a native Koreans after an oral 400 mg dose of chlorzoxazone administered to 128 subjects. Urine samples were collected during the subsequent 8-hour period and urinary concentrations of chlorzoxazone and 6-hydroxychlorzoxazone were determined by a high performance liquid chromatography with an ultraviolet detector. The limit of detection in the samples was found to be 0.5 mug/ml. The mean value of the 6-hydroxychlorzoxazone excreted in 8 hr urine expressed as the percentage was 48.2 13.8%. The frequency distribution of percentage of the administered dose excreted as the 6-hydroxy metabolite was unimodally distributed in the subjects studied. However, the values showed wide (7-fold) interindividual difference, ranged from 11.6% to 79.8% of the dose of chlorzoxazone. Thus, it was considered that the pharmacogenetic characteristics of CYP2E1 in a Korean population did not-represent multimodal distribution in the 6-hydroxychlorzoxazone excreted in 8-hr urine expressed as the percentage. And the activity of the CYP2E1 in a Korean population seemed to be less compared with that of the Caucasian subjects.

Pharmacokinetics of fluoxetine and its effects on cytochrome P450 isoenzymes / 中国药理学通报

Fluoxetine is a relatively novel class of selective serotonin reuptake inhibitors (SSRIs) with antidepressant properties. It seems to facilitate serotonergic transmission via down regulation of presynaptic inhibitory autoreceptors, with no effect on muscarinic receptors and doubtful effects on ? adrenergic receptors. Fluoxetine is mainly metabolized by cytochrome P450 (CYP) isoenzymes. It has been shown that CYP2C9、CYPD6, and CYP2C19 are major CYP isoforms responsible for the N demethylation of fluoxetine. Since both fluoxetine and its main metabolite norfluoxetine are the inhibitors of CYP2D6, CYP3A4, CYP2C9, and CYP2C19, there are some drug drug interactions of fluoxetine with other drugs for metabolism by those CYP isoenzymes, which results in interindividual differences in the pharmacokinetics and efficacy.