Pharmacology & toxicology最新文献_第7页

Paraquat-induced membrane dysfunction in pulmonary microvascular endothelial cells. 百草枯诱导的肺微血管内皮细胞膜功能障碍。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-19.x

M Tsukamoto, Y Tampo, M Sawada, M Yonaha

{"title":"Paraquat-induced membrane dysfunction in pulmonary microvascular endothelial cells.","authors":"M Tsukamoto, Y Tampo, M Sawada, M Yonaha","doi":"10.1034/j.1600-0773.2000.d01-19.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-19.x","url":null,"abstract":"Membrane dysfunction monitored by lactate dehydrogenase release from cultured pulmonary microvascular endothelial cells of pigs, which were exposed to paraquat at different concentrations (0.1-2 mM), was examined. Paraquat caused a time-dependent increase in lactate dehydrogenase release. Lactate dehydrogenase releases after 72 hr, 32, 58, and 84% by 0.1, 0.5, and 2 mM paraquat, respectively, were well correlated with cell viability measured by cell adherence. In contrast, reductions of two tetrazolium compounds were depleted profoundly by 72 hr after exposure to 0.5 mM paraquat, suggesting depletion of intracellular reductive substances. Extracellular hydrogen peroxide began to significantly increase 56 hr or 32 hr after exposure to 0.5 mM or 1.5 mM paraquat, respectively, preceding the initial increase of lactate dehydrogenase release (64 hr by 0.5 mM or 48 hr by 1.5 mM). Lactate dehydrogenase release 72 hr after exposure to 0.5 mM paraquat was prevented strongly by catalase (1000 units/ml), but weakly by superoxide dismutase (1000 units/ml). These enzymes failed to restore the reduced acid phosphatase activity. Also, 0.1 mM desferal or alpha,alpha'-dipyridyl protected lactate dehydrogenase release. Similarly, 1 mM thiourea or dimethylthiourea, and 0.5 mM alpha-tocopherol or trolox, were effective, but diethylenetriaminepentaacetic acid (0.1 mM) and probucol (5 or 10 microM) were ineffective. Exposure of 0.5 or 1.5 mM paraquat suppressed levels of lipid peroxidation. These results indicate that membrane dysfunction by paraquat is ascribed to an iron-catalyzed reaction of extracellularly increased hydrogen peroxide. A deleterious species for the membrane dysfunction is discussed.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"102-9"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21602924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

Ceramides that mediate apoptosis reduce glucose uptake and transporter affinity for glucose in human leukaemic cell lines but not in neutrophils. 介导细胞凋亡的神经酰胺在人白血病细胞系中减少葡萄糖摄取和转运体对葡萄糖的亲和力，但在中性粒细胞中没有。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-21.x

N Ahmed, M V Berridge

{"title":"Ceramides that mediate apoptosis reduce glucose uptake and transporter affinity for glucose in human leukaemic cell lines but not in neutrophils.","authors":"N Ahmed, M V Berridge","doi":"10.1034/j.1600-0773.2000.d01-21.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-21.x","url":null,"abstract":"We have demonstrated that CD95-induced apoptosis in a human leukaemic T-cell line resulted in loss of glucose transporter function (Berridge et al. 1996). To determine whether ceramide, a mediator of CD95 and tumour necrosis factor-alpha-induced apoptosis, has similar effects on glucose transport, the human leukaemic cell lines, Jurkat and U937, and human peripheral blood neutrophils were treated with ceramide or sphingomyelinase and the effects on glucose transport determined by measuring [3H]-2-deoxyglucose uptake. We show that in U937 and Jurkat cells, the cell permeable ceramides, C2 (N-acetylsphingosine) and C6 (N-hexanoylsphingosine) inhibit glucose uptake within minutes of initiating ceramide treatment, 60-70% inhibition being observed within 2 hr. Loss of glucose transport correlated with loss of proliferative response, but metabolic activity as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction, was affected to a much lesser extent. With Jurkat and U937 cells, the inhibitory effects of ceramides on glucose transport were associated with reduced affinity of glucose transporters for glucose (Km). Similar effects were observed with sphingomyelinase. With human peripheral blood neutrophils, C2 and C6-ceramides inhibited glucose uptake by 70-80% within 30 min. without affecting transporter affinity for glucose, but the maximum velocity of uptake (Vmax) was reduced. These results show that acute regulation of glucose transport is an early effector mechanism of cell death induced by ceramides in human leukaemic cell lines and peripheral blood neutrophils. This is the first study which describes ceramide-induced early physiological/biochemical events leading to cell death in human cells.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"114-21"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21602926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Involvement of CYP3A4 in the metabolism of bromperidol in vitro. CYP3A4参与溴哌啶醇体外代谢。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-27.x

S Sato, T Someya, O Shioiri, T Koitabashi, Y Inoue

引用次数: 5

Hypotensive activity of the pineal indoleamine hormones melatonin, 5-methoxytryptophol and 5-methoxytryptamine. 松果体吲哚胺激素褪黑激素、5-甲氧基色氨酸和5-甲氧基色胺的降压活性。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-23.x

H Wang, T B Ng

{"title":"Hypotensive activity of the pineal indoleamine hormones melatonin, 5-methoxytryptophol and 5-methoxytryptamine.","authors":"H Wang, T B Ng","doi":"10.1034/j.1600-0773.2000.d01-23.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-23.x","url":null,"abstract":"Injection of the pineal indoles melatonin, 5-methoxytryptophol and 5-methoxytryptamine via the external jugular vein elicited a dose-dependent depression in mean arterial pressure. Melatonin and 5-methoxytryptophol were approximately equipotent and a dose of 150 micromol/kg brought about a reduction of about 40 mmHg in mean arterial pressure. Methoxytryptamine exerted a much more potent hypotensive action. An abrupt decrement in mean arterial pressure by 30 mmHg occurred when the dose was only 2 nmol/kg. Subsequent increases in the dose further lowered the mean arterial pressure, but more gently. The other pineal indoles tested including 5-methoxyindoleacetic acid and 5-hydroxyindoleacetic acid, as well as 6-methoxy-2-benzoxazolinone, did not affect the mean arterial pressure when tested up to 80 micromol/kg. Methylene blue, a guanylate cyclase inhibitor, was not able to antagonize the hypotensive activity of melatonin, suggesting that the mechanism of action of melatonin does not involve guanylate cyclase. Lidocaine, which blocks sodium channels in perivascular nerves, antagonized the hypotensive action of melatonin.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"125-8"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21602928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Nitric oxide protects murine embryonic liver cells (BNL CL.2) from cytotoxicity induced by glucose deprivation. 一氧化氮保护小鼠胚胎肝细胞(BNL CL.2)免受葡萄糖剥夺引起的细胞毒性。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-26.x

H O Pae, H G Kim, Y S Paik, S G Paik, Y M Kim, G S Oh, H T Chung

{"title":"Nitric oxide protects murine embryonic liver cells (BNL CL.2) from cytotoxicity induced by glucose deprivation.","authors":"H O Pae, H G Kim, Y S Paik, S G Paik, Y M Kim, G S Oh, H T Chung","doi":"10.1034/j.1600-0773.2000.d01-26.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-26.x","url":null,"abstract":"We investigated the protective effects of nitric oxide on cell death of murine embryonic liver cells (BNL CL.2) after glucose deprivation. Endogenous nitric oxide production by BNL CL.2 cells was induced by 6 hr pretreatment with interferon-gamma and lipopolysaccharide. We used sodium nitroprusside and S-nitroso-L-glutathione as exogenous nitric oxide-generating compounds. All agents were used at doses that did not show direct cytotoxicity as measured by crystal violet staining assay. In the BNL CL.2 cells, the viability dropped very steeply after 24 hr incubation with glucose-free media. Endogenous nitric oxide produced by treatment of the cells with interferon-gamma and lipopolysaccharide protected the cells from glucose deprivation-induced cytotoxicity, but did not protect them in the presence of the nitric oxide synthesis inhibitor, N(G)-monomethyl-L-arginine. Exogenous nitric oxide protected the cells from glucose deprivation-induced cytotoxicity in a concentration-dependent manner. Cytoprotection by nitric oxide donors was abolished by the use of nitric oxide scavenger, 2-phenyl-4,4,5,5,-tetramethylimidazole, but not by the soluble guanosine cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. In addition, cytoprotective effects comparable to endogenous or exogenous nitric oxide were not observed when the cells were incubated with dibutyl guanosine 3',5'-cyclic monophosphate. Based upon these results, we suggest that nitric oxide may enhance the cell survival of BNL CL.2 cells after glucose deprivation via a guanosine 3',5'-cyclic monophosphate-independent pathway.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"140-4"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21603464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Minimal toxicity to myeloid progenitor cells of weekly 24-hr infusion of high-dose 5-fluorouracil: direct evidence from colony forming unit-granulocyte and monocyte (CFU-GM) clonogenic assay. 每周24小时输注高剂量5-氟尿嘧啶对髓系祖细胞的最小毒性:来自集落形成单位-粒细胞和单核细胞(CFU-GM)克隆生成试验的直接证据。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-22.x

K H Yeh, S H Yeh, Y S Chang, A L Cheng

{"title":"Minimal toxicity to myeloid progenitor cells of weekly 24-hr infusion of high-dose 5-fluorouracil: direct evidence from colony forming unit-granulocyte and monocyte (CFU-GM) clonogenic assay.","authors":"K H Yeh, S H Yeh, Y S Chang, A L Cheng","doi":"10.1034/j.1600-0773.2000.d01-22.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-22.x","url":null,"abstract":"Although very high doses of 5-fluorouracil was used in the weekly 24-h infusion, high-dose 5-fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit-granulocyte and monocyte clonogenic assay; and 2 representative modes of 5-fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5-fluorouracil in the bone marrow to be 200-400 microM and 1-2 microM for the 30 min. infusion (600-900 mg/m2) and the 24 hr-infusion (1000-2000 mg/m2) regimens, respectively. The results of our colony-forming unit-granulocyte and monocyte clonogenic assay showed that 24-hr exposure to 5-fluorouracil (2 microM) and 30 min. exposure to 5-fluorouracil (100 microM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"122-4"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21602927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Effects of various aluminium compounds given orally to mice on Al tissue distribution and tissue concentrations of essential elements. 口服不同铝化合物对小鼠铝组织分布及组织中必需元素浓度的影响。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-25.x

M Długaszek, M A Fiejka, A Graczyk, J C Aleksandrowicz, M Slowikowska

{"title":"Effects of various aluminium compounds given orally to mice on Al tissue distribution and tissue concentrations of essential elements.","authors":"M Długaszek, M A Fiejka, A Graczyk, J C Aleksandrowicz, M Slowikowska","doi":"10.1034/j.1600-0773.2000.d01-25.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-25.x","url":null,"abstract":"To evaluate the risk of gastrointestinal long-term aluminium (Al) exposure, aluminium distribution and the levels of the following essential elements: Ca, Mg, Zn, Cu, and Fe in tissue were studied. Aluminium was administered in drinking water as aluminium chloride, dihydroxyaluminium sodium carbonate or aluminium hydroxide. Mice (strain Pzh:SFIS) were exposed to a total dose of 700 mg Al in long-term treatment (for each Al compound n = 15). Concentrations of Al, Ca, Mg, Zn, Cu, and Fe in stomach, kidneys, bone and liver were analyzed by atomic absorption spectrometry. After AlCl3 treatment, aluminium was found to accumulate in all tested tissues. A significant decrease in Fe concentration in liver and Zn in kidneys was observed in comparison to concentrations of these elements in the control group. In the Al(OH)3-treated group, accumulation of aluminium was observed in bone only and decline of Fe concentration in stomach and Cu in liver and kidney. In the NaAl(OH)2CO3-treated group the increase in Al concentration was significant in bone; there was no change in concentration of essential elements in the examined tissues. The observed aluminium accumulation was not accompanied by changes in Ca and Mg concentration except for bone. This study showed that oral administration as a route of Al exposure can result in diverging accumulation of aluminium in tissues, the concentration depending on the chemical form.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"135-9"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21602930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20

Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes. 氟他胺对大鼠和人原代肝细胞遗传毒性的评价。

Pharmacology & toxicology Pub Date : 2000-03-01 DOI: 10.1034/j.1600-0773.2000.d01-24.x

A Martelli, G B Campart, R Carrozzino, M Ghia, F Mattioli, E Mereto, P Orsi, C P Puglia

{"title":"Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes.","authors":"A Martelli, G B Campart, R Carrozzino, M Ghia, F Mattioli, E Mereto, P Orsi, C P Puglia","doi":"10.1034/j.1600-0773.2000.d01-24.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-24.x","url":null,"abstract":"Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes. In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-glutamyltraspeptidase-positive foci were detected only in 3 of 10 rats. There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks. In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 microM. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic drug.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 3","pages":"129-34"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21602929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 12

Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells. 洛伐他汀通过激活白血病HL-60细胞的caspase-3和DNase II诱导细胞凋亡。

Pharmacology & toxicology Pub Date : 2000-02-01 DOI: 10.1034/j.1600-0773.2000.d01-16.x

I K Wang, S Y Lin-Shiau, J K Lin

{"title":"Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells.","authors":"I K Wang, S Y Lin-Shiau, J K Lin","doi":"10.1034/j.1600-0773.2000.d01-16.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-16.x","url":null,"abstract":"Lovastatin, an HMG-CoA reductase inhibitor, was found to suppress growth and induce apoptosis in culture human promyelocytic leukaemic cell, HL-60. However, the mechanisms of lovastatin-induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin-induced apoptosis in HL-60 cells in a dose- and time-dependent manner. The features of this apoptosis were attenuated by the presence of mevalonate, a metabolic intermediate of cholesterol synthesis. Treatment of lovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase-3, but not caspase-1 activity. Lovastatin also stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP), and followed by the appearance of caspase activity and DNA fragmentation. Pretreatment with caspase-3 inhibitors, Ac-DEVD-CHO and Z-VAD-FMK, inhibited lovastatin induced caspase-3 activity and DNA fragmentation. Furthermore, we demonstrated that DNase II was involved in the DNA fragmentation induced by lovastatin. These results suggested that the mechanism of lovastatin induced HL-60 cells apoptosis through activation of caspase-3 and DNase II activities.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 2","pages":"83-91"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21580207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 30

Differential activities of CYP1A isozymes in hepatic and intestinal microsomes of control and 3-methylcholanthrene-induced rats. 对照和3-甲基胆碱诱导大鼠肝脏和肠道微粒体中CYP1A同工酶的活性差异。

Pharmacology & toxicology Pub Date : 2000-02-01 DOI: 10.1034/j.1600-0773.2000.d01-14.x

M Spatzenegger, Y Horsmans, R K Verbeeck

{"title":"Differential activities of CYP1A isozymes in hepatic and intestinal microsomes of control and 3-methylcholanthrene-induced rats.","authors":"M Spatzenegger, Y Horsmans, R K Verbeeck","doi":"10.1034/j.1600-0773.2000.d01-14.x","DOIUrl":"https://doi.org/10.1034/j.1600-0773.2000.d01-14.x","url":null,"abstract":"Differences in expression of CYP1A isoforms (CYP1A1 and CYP1A2) in liver and small intestine of male Wistar rats and their inducibility by 3-methylcholanthrene as well as the effect of different CYP1A1/1A2 expression on caffeine metabolism were investigated. In rat liver, CYP1A2 is the predominant isoform and CYP1A1 protein expression in liver is significantly increased after treatment by 3-methylcholanthrene. In contrast, only CYP1A1 was detected in control and 3-methylcholanthrene induced small intestine microsomes. Treatment with 3-methylcholanthrene (40 mg/kg intraperitoneally daily during 1, 2, 3 or 4 days) demonstrated that liver CYP1A1 is more sensitive for the induction effects than CYP1A2 and also that significant induction of CYP1A1 in rat small intestine only occurred after 3 to 4 days pretreatment. Caffeine metabolism and inhibition studies by furafylline, CYP1A1 antiserum and ketoconazole revealed that the differences in the expression of CYP1A1 and CYP1A2 in the two tissues led to significant changes in the contribution of the various isoenzymes involved in the biotransformation of caffeine. Whereas in liver paraxanthine formation was almost exclusively catalyzed by CYP1A2, in rat proximal intestine it was formed by CYP1A1. In addition, other CYP enzymes (most probably CYP3A) play a significant role in theobromine and theophylline formation from caffeine in rat intestine. Overall, this study shows different expression and inducibility of CYP1A1/1A2 by 3-methylcholanthrene in rat liver and small intestine. Furthermore in rat intestine cytochrome P450 isozymes such as CYP1A1 and CYP3A replace CYP1A2 in the caffeine metabolism.","PeriodicalId":19876,"journal":{"name":"Pharmacology & toxicology","volume":"86 2","pages":"71-7"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21580205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 21