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The developing organism lacks many of the cytochrome P450 isoforms detected in the adult, or they are expressed at very low levels. It remains controversial whether P450 gene regulatory mechanisms are present prenatally. As a result, the catalytic function of P450s in fetal tissues has been questioned. The aim of our study was to evaluate CYP: 1A1, 1A2, 2B1/2, 2E1, 3A1 and 3A2 expression in livers of 18- and 20-days-old fetuses, and newborns from untreated and P-naphthoflavone-, phenobarbital-, dexamethasone- or ethanol-treated Sprague-Dawley rats. CYP expressions were evaluated at both tran­scriptional (RT-PCR) and protein (Western blotting) levels. CYP mRNA expressions were detected on day 18 of gestation. CYP: 1A1, 2B1/2 and 3A1 proteins were found on day 18; CYP2E1 protein - on day 20; 1A2 and 3A2 protein - in newborn livers. Studied P450s demonstrated a very low expression in animal tissues before and just after birth but, in most cases, they were inducible. It is concluded that the inductory mechanisms of CYP: 1A1, 2B1/2, 3A1/2 and 2E1 but not CYP1A2, are functional in fetal liver at transcriptional or translational levels. The effects of metabolic activation of CYP1A2 substrates may be reduced in fetuses.
Four-month-old female Wistar rats were exposed for 20 days to tobacco smoke obtained from non-filter cigarettes. During the exposure, concentration of tobacco smoke was monitored indirectly by measuring the CO level (1500 mg/m3 air). The efficacy of exposure was assessed by measuring urine nicotine and cotinine levels. Cigarette smoke did not change total cytochrome P450 and b5 protein levels in any of the organs studied, and most of these organs did not show any changes in the activity of reductases associated with these cytochromes. Following exposure to tobacco smoke, fetal rat liver expressed CYP2B1/2 protein; in newborns (day 1) both liver and lung showed CYP2B1/2 protein expression and very low pentoxyresorufin O-dealkylase activity. Western blot analysis of adult liver, lung, heart, but not of brain microsomes, showed that tobacco smoke induced CYP2B1/2 in both nonpregnant and pregnant rats, though its expression was lower in the livers and hearts of pregnant females. In the rat and human placenta, neither rat CYP2B1/2 nor human CYP2B6 showed basal or tobacco smoke-induced expression at the protein level. This study shows clearly that the expression of CYP2B1/2, which metabolizes nicotine and some drugs and activates carcinogens, is controlled in rats by age-, pregnancy-, and tissue-specific regulatory mechanisms.
The aim of the study was to evaluate the effect of acetaminophen (APAP) and/or trichloroethylene (TRI) on the liver cytochrome P450-dependent monooxygenase system, CYP2E1 and CYP1A2 (two important P450 isoforms), and liver glutathione (GSH) content in rats. Rats were given three different doses of APAP (250, 500 and 1000 mg/kg b...) and then the above-mentioned parameters were measured for 48 h. The lowest APAP dose produced small changes in the cytochrome P450 content of liver. At 500 mg/kg APAP increased the cytochrome P450 content to 230% of the control. The inductive effect was seen at 1000 mg/kg dose but at 24 h and later. NADPH-cytochrome P450 reductase activity was the highest after the lowest dose of APAP, while after the highest dose it was equal to the control value. TRI increased both the cytochrome P450 content and the NADPH-cytochrome P450 reductase activity. When TRI was combined with APAP, both these parameters increased in the first hours of observation, but they returned to the control values at 24 h. When APAP was given at 250 mg/kg, GSH levels decreased to 55% of the control at 8 h and returned to the control values at 24 h. The higher doses of APAP decreased GSH levels more than the lowest dose, but after 24 h GSH levels did not differ from those of the control. When TRI was given at 250 mg/kg, the GSH levels decreased to 68% of the control at 2 h and then they increased gradually and tended to exceed the control values at 48 h. The effect of TRI combined with APAP on the level of GSH was virtually the same as that of APAP alone given at 500 mg/kg.
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