Tobacco smoke (TS) was described as a mixture of numerous cytochrome P450 (P450) substrates, inducers, and inhibitors. These inducers and inhibitors may modify drug clearance and xenobiotic or endogenous metabolism affecting P450s expression. In the present study, the effect of gestation and TS on: (1) cytochrome P450 CYP1A1, CYP1A2, and CYP2E1 protein expressions, and (2) cytochrome P450-linked microsomal enzyme activities, were studied in fetal rat liver, rat, and human placenta and in newborn and adult rat hepatic and extrahepatic tissues. Non-pregnant and pregnant 4-month-old female Wistar rats were exposed to TS (500, 1,000, or 1,500 mg carbon monoxide per m(3) air) in a toxicological chamber for 3 weeks (6 h daily, 5 days weekly). Human placentas were sampled from non-smoking, passive smoking, or active smoking primiparas. The efficacy of exposure was assessed by measuring urine cotinine levels. The TS-dependent inductory effect on the expression of CYP1A1 and 1A2 and related monooxygenase activities, and the inhibitory/inductory effect on CYP2E1 expression in rat tissues were observed. Pregnancy was associated with decreased levels of constitutive CYP1A1 and 2E1 in hepatic and extrahepatic tissues, TS-inducible CYP1A2 expression in the liver, and CYP1A1 expression in lungs and heart, but had no inhibitory effect on TS-inducible CYP1A1 and 2E1 expression, EROD, and P450-cooperated enzyme activities in the liver, kidney, and, in the latter case, in the heart. The presence of TS-induced CYP1A1 protein was confirmed in rat and human placenta and showed in newborn liver and lungs. CYP1A2 and 2E1 proteins were detectable in fetal rat liver. It was concluded that the expression of CYP1A1, 1A2, and 2E1, which metabolize some drugs and activate carcinogens, is controlled by age-, pregnancy-, and tissue-specific regulatory mechanisms in rats. Gestational differences in the regulation of expression of CYP1A subfamily members are not excluded. CYP1A1 and 2E1, but not CYP1A2 inductory mechanisms seem to be functional in fetal liver at day 21 of pregnancy but they appeared to be uninducible under a TS exposure. In TS-exposed pregnant females and fetuses the effects of metabolic activation of CYP1A1 and 1A2 substrates might be reduced because of lower CYP expressions or poor induction, respectively.
Non-differentiated cells are attractive targets for cell therapy. During liver regeneration oval cells intensively proliferate and differentiate extending their metabolic activity. Hepatic cytochromes P450 (CYPs) can be linked either with metabolic activation of toxic compounds or drug metabolism. We investigated the differentiation and biotransformative potential of non-differentiated cells in primary cell cultures isolated from livers of fetuses (16-days-old), young (4-monthsold) and old (20-months-old) rats. Under the conditions of experimental hepatocarcinogenesis, adult rats were fed for three weeks with CDE diet. Liver cells were cultured and precursor cells were differentiated to hepatocytes following induction with sodium butyrate (SB) or dimethyl sulphoxide (DMSO) in culture on MesenCult medium. We identified a number of cells expressing Thy-1, CD34, α-fetoprotein, cytokeratines -CK18 or CK19 and glutathione transferases -GSTπ or GSTα. In vitro differentiation of these cells, isolated from CDE-treated rats begun earlier as compared to non-treated ones. Agedependent changes in the cell differentiation sequence, as well as CYPmRNA expression sequence accompanying precursor cells differentiation, were also observed. mRNA expression of CYP1A2, CYP2B1/2 and CYP3A1 was higher in the cells of young rats, but in the case of CYP2E1 -in the cells of old rats. It was concluded that both proliferation and differentiation potential of oval cells, decreased with age.Key words: cytochromes P450, oval cells, cell differentiation, experimental hepatocarcinogenesis, liver regeneration.Correspondence: P. Czekaj, Dept. of Histology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland; tel.: (+4832) 2088374, fax.: (+4832) 2526574, e-mail: pcz@sum.edu.pl Abbreviations: AFP α-fetoprotein; BrdU -bromodeoxyuridin; CDE diet -choline-deficient ethionine-supplemented diet; CK18 and CK19 -cytokeratines CK18 and CK19; DCL(s) -differentiation cell lineage(s); CYP(s) -cytochrome(s) P450; DMSOdimethyl sulphoxide; GSTα -glutathione S transferase α; GSTπ -glutathione S transferase π; L-PK -pyruvate kinase isoform α; M 2 PK -pyruvate kinase; 4m and 20m -4-and 20-month-old rats, respectively; IOD -integrated optical density; SB -sodium butyrate.
It has been established beyond doubt that, as well as the liver, the small intestine is an important site of first-pass metabolism of numerous drugs, food components and toxic xenobiotics. However, there is not much information available about age-dependent changes of intestinal biotransformation pathways. In the present paper, we evaluated the relationships between intestinal cytochrome P450 complex activity and the age of animals. The study was carried out on male Sprague-Dawley rats (n = 5) from 5 age series: 0.5-, 2-, 4-, 20-, and 28 months old. Animals at every age series were divided into 4 groups: control and three groups of rats treated with the CYP450 specific inducers: phenobarbital, b-naphtoflavone and dexamethasone, respectively. RNA was isolated from intestinal mucosa, and then standard RT-PCR was used for the analysis of CYP1A1, CYP2B1/2 and CYP3A1 mRNA expression. Additionally, the activities of NADPH-cytochrome P450 and NADH-cytochrome b 5 reductases in the microsomal fraction were biochemically estimated. The constitutive intestinal CYP1A1 mRNA expression changes during maturation and aging. Inducibility of CYP1A1 gene was evident in intestinal mucosa at 2-, 4-and 20-month-old rats. A similar pattern of changes was observed for CYP2B1/2 isoforms. CYP3A1 mRNA expression was not detected in small intestine of 2-week-old rats. In matured rats, constitutive intestinal CYP3A1 expression was low, although after induction, significant increases in CYP3A1 mRNA amount were noted in aged individuals. Intestinal activity of both analyzed reductases was lowest in immature rats and highest in 28-month-old animals. In conclusion, the activity of cytochrome P450 complex in rat small intestine was not decreased by the aging processes, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage.
Neuroleptic-induced reduction in the expression of thalamic NMDA-R subunits may play an important role in the regulation of glutamatergic transmission disorders in cortico-striato-thalamo-cortical loop in schizophrenia. A decrease in NMDA signaling in this region after long-term neuroleptic administration may also cautiously explain the incomplete effectiveness of these drugs in the therapy of schizophrenia-related cognitive disturbances.
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