Ellipticine is a pro-drug, whose activation is dependent on its oxidation by cytochromes P450 (CYP) and peroxidases. Cytochrome b(5) alters the ratio of ellipticine metabolites formed by isolated reconstituted CYP1A1 and 1A2, favoring formation of 12-hydroxy- and 13-hydroxyellipticine metabolites implicated in ellipticine-DNA adduct formation, at the expense of 9-hydroxy- and 7-hydroxyellipticine that are detoxication products. Cytochrome b(5) enhances the production of 12-hydroxy and 13-hydroxyellipticine. The change in metabolite ratio results in an increased formation of covalent ellipticine-DNA adducts, one of the DNA-damaging mechanisms of ellipticine antitumor action. This finding explains previous apparent discrepancies found with isolated enzymes and in vivo, where CYP1A enzymatic activation correlated with ellipticine-DNA-adduct levels while isolated CYP1A1 or 1A2 in reconstituted systems were much less effective than CYP3A4. The effect of cytochrome b(5) might be even more pronounced in vivo, since, as we show here, ellipticine increases levels of cytochrome b(5) in rat liver. Our results demonstrate that both the native 3D structure of cytochrome b(5) and the presence of the heme as an electron transfer agent in this protein enable a shift in ellipticine metabolites formed by CYP1A1/2.

• MeSH
• adukty DNA metabolismus   MeSH
• antitumorózní látky fytogenní chemie   metabolismus   farmakologie   MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP1A2 MeSH
• cytochromy metabolismus   MeSH
• elipticiny chemie   metabolismus   farmakologie   MeSH
• hemoproteiny metabolismus   MeSH
• injekce intraperitoneální MeSH
• jaterní mikrozomy účinky léků   enzymologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• metabolická inaktivace MeSH
• oxidace-redukce MeSH
• potkani Wistar MeSH
• proteiny vázající hem MeSH
• transportní proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• antitumorózní látky fytogenní MeSH
• Cyp1a2 protein, rat MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• cytochromy MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• hemoproteiny MeSH
• proteiny vázající hem MeSH
• transportní proteiny MeSH

Aristolochic acid (AA) causes aristolochic acid nephropathy, Balkan endemic nephropathy, and their urothelial malignancies. To identify enzymes involved in the metabolism of aristolochic acid I (AAI), the major toxic component of AA we used HRN (hepatic cytochrome P450 [Cyp] reductase null) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes. AAI was demethylated by hepatic Cyps in vitro to 8-hydroxy-aristolochic acid I (AAIa), indicating that less AAI is distributed to extrahepatic organs in wild-type (WT) mice. Indeed, AAI-DNA-adduct levels were significantly higher in organs of HRN mice, having low hepatic AAI demethylation capacity, than in WT mice. Absence of AAI demethylation in HRN mouse liver was confirmed in vitro; hepatic microsomes from WT, but not from HRN mice, oxidized AAI to AAIa. To define the role of hepatic Cyps in AAI demethylation, modulation of AAIa formation by CYP inducers was investigated. We conclude that AAI demethylation is attributable mainly to Cyp1a1/2. The higher AAI-DNA adduct levels in HRN than WT mice were the result of the lack of hepatic AAI demethylation concomitant with a higher activity of cytosolic NAD(P)H:quinone oxidoreductase (Nqo1), which activates AAI. Mouse hepatic Cyp1a1/2 also activated AAI to DNA adducts under hypoxic conditions in vitro, but in renal microsomes, Por and Cyp3a are more important than Cyp1a for AAI-DNA adduct formation. We propose that AAI activation and detoxication in mice are dictated mainly by AAI binding affinity to Cyp1a1/2 or Nqo1, by their turnover, and by the balance between oxidation and reduction of AAI by Cyp1a.

• MeSH
• adukty DNA MeSH
• biotransformace MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• játra enzymologie   metabolismus   MeSH
• karcinogeny farmakokinetika   MeSH
• krysa rodu Rattus MeSH
• kyseliny aristolochové farmakokinetika   MeSH
• lidé MeSH
• metylace MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa genetika   metabolismus   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• aristolochic acid I MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• karcinogeny MeSH
• kyseliny aristolochové MeSH
• NADPH-cytochrom c-reduktasa MeSH

OBJECTIVE: Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of action. This anticancer agent should be considered a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation to species forming covalent DNA adducts. The target of this study was to investigate a role of CYP and peroxidase enzymes in ellipticine oxidative activation in rats, a suitable model mimicking the fate of ellipticine in humans, in details. The contribution of pulmonary and renal CYP- and peroxidase enzymes to ellipticine metabolic activation is investigated and compared with that found in the liver. METHODS: Ellipticine oxidation and DNA adduct formation in vitro were investigated using microsomes isolated from liver, lung and kidney of rats, either control (untreated) or treated i.p. with a single dose of 40 mg of ellipticine per kg of body weight. HPLC with UV detection was employed for the separation and characterization of ellipticine metabolites. Inhibitors of CYPs and cyclooxygenase (prostaglandin H synthase, COX) were used to characterize the enzymes participating in ellipticine oxidative activation in rat liver, lung and kidney. Ellipticine-derived DNA adducts were detected by 32P-postlabeling. RESULTS: Using α-naphthoflavone, furafylline and ketoconazole, inhibitors of CYP1A, 1A2 and 3A, respectively, we found that the CYP1A and 3A enzymes play a major role in ellipticine activation to species forming DNA adducts in liver microsomes. Because of lower expression of these enzymes in lungs and kidneys, even after their induction by ellipticine, they play a minor role in ellipticine activation in these extrahepatic tissues. Arachidonic acid, a cofactor of COX, increased ellipticine activation in the microsomes of extrahepatic tissues. In addition, indomethacin, an inhibitor of COX, efficiently inhibited formation of ellipticine-derived DNA adduct in these microsomes. Based on these results, we attribute the higher activation of ellipticine in lung and kidney microsomes to COX than to CYP enzymes. CONCLUSION: The results demonstrate that whereas CYP enzymes of 1A and 3A subfamilies are the major enzymes activating ellipticine in rat livers, peroxidase COX plays a significant role in this process in lungs and kidneys.

• MeSH
• adukty DNA účinky léků   MeSH
• antitumorózní látky metabolismus   MeSH
• biotransformace účinky léků   MeSH
• elipticiny metabolismus   MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny metabolismus   MeSH
• mikrozomy účinky léků   metabolismus   MeSH
• modely u zvířat MeSH
• oxidace-redukce účinky léků   MeSH
• peroxidasy fyziologie   MeSH
• plíce metabolismus   MeSH
• potkani Wistar MeSH
• systém (enzymů) cytochromů P-450 fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• antitumorózní látky MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• peroxidasy MeSH
• systém (enzymů) cytochromů P-450 MeSH

A simple and sensitive method was developed to separate the carcinogenic polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), and six of its oxidation metabolites generated by rat hepatic microsomes enriched with cytochrome P450 (CYP) 1A1, by high pressure liquid chromatography (HPLC). The HPLC method, using an acetonitrile/water gradient as mobile phase and UV detection, provided appropriate separation and detection of both mono- and di-hydroxylated metabolites of BaP as well as BaP diones formed by rat hepatic microsomes and the parental BaP. In this enzymatic system, 3-hydroxy BaP, 9-hydroxy BaP, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-9,10-dihydrodiol and BaP-dione were generated. Among them the mono-hydroxylated BaP metabolite, 3-hydroxy BaP followed by di-hydroxylated BaP products, BaP-7,8-dihydrodiol and BaP-9,10-dihydrodiol, predominated, while BaP-dione was a minor metabolite. This HPLC method will be useful for further defining the roles of the CYP1A1 enzyme with both in vitro and in vivo models in understanding its real role in activation and detoxification of BaP.

• Klíčová slova
• HPLC, benzo[a]pyrene, metabolism,
• Publikační typ
• časopisecké články MeSH

Cytochrome b(5) (b(5)) has been shown to modulate many cytochrome P450 (CYP)-dependent reactions. In order to elucidate the mechanism of such modulations, it is necessary to evaluate not only the effect of native b(5) on CYP-catalyzed reactions, but also that of the apo-cytochrome b(5) (apo-b(5)). Therefore, the apo-b(5) protein was prepared using a heterologous expression in Escherichia coli. The gene for rabbit b(5) was constructed from synthetic oligonucleotides using polymerase chain reaction (PCR), cloned into pUC19 plasmid and amplified in DH5 alpha cells. The gene sequence was verified by DNA sequencing. The sequence coding b(5) was cleaved from pUC19 by NdeI and XhoI restriction endonucleases and subcloned to the expression vector pET22b. This vector was used to transform E. coli BL-21 (DE3) Gold cells by heat shock. Expression of b(5) was induced with isopropyl beta-D-1-thiogalactopyranoside (IPTG). The b(5) protein, produced predominantly in its apo-form, was purified from isolated membranes of E. coli cells by chromatography on a column of DEAE-Sepharose. Using such procedures, the homogenous preparation of apo-b(5) protein was obtained. Oxidized and reduced forms of the apo-b(5) reconstituted with heme exhibit the same absorbance spectra as native b(5). The prepared recombinant apo-b(5) reconstituted with heme can be reduced by NADPH:CYP reductase. The reconstituted apo-b(5) is also fully biologically active, exhibiting the comparable stimulation effect on the CYP3A4 enzymatic activity towards oxidation of 1-phenylazo-2-hydroxynaphthalene (Sudan I) as native rabbit and human b(5).

• MeSH
• apoenzymy genetika   metabolismus   MeSH
• chromatografie iontoměničová MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• cytochromy b5 genetika   metabolismus   MeSH
• Escherichia coli genetika   MeSH
• hem metabolismus   MeSH
• klonování DNA MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• naftoly metabolismus   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• sekvence nukleotidů MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-phenylazo-2-naphthol MeSH Prohlížeč
• apoenzymy MeSH
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochromy b5 MeSH
• hem MeSH
• naftoly MeSH
• rekombinantní proteiny MeSH
• systém (enzymů) cytochromů P-450 MeSH

OBJECTIVES: Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of its action. Recently, we have found that 13-hydroxyellipticine, formed from ellipticine as the predominant metabolite in human livers, is bound to deoxyguanosine in DNA, generating the major DNA adduct in vivo and in vitro. The development of the methods suitable for the preparation of this adduct in the amounts sufficient for identification of its structure and those for its isolation and partial characterization is the aim of this study. METHODS: High performance liquid chromatography (HPLC) was employed for separation of 13-hydroxyellipticine-mediated deoxyguanosine adduct. The 32P-postlabeling technique was utilized to detect this adduct in DNA. RESULTS: The formation of the 13-hydroxyellipticine-derived deoxyguanosine adduct in DNA in vitro was increased under the alkaline pH of the incubations and by the formation of the sulfate and acetate conjugates of 13-hydroxyellipticine generated by reactions with 3'-phosphoadenosine-5'-phosphosulfate (PAPS) or acetyl-coenzyme A (acetyl-CoA) catalyzed by human sulfotransferases (SULTs) 1A1 and 1A2 and N,O-acetyltransferases (NATs) 1 and 2. The HPLC method suitable for separation the 13-hydroxyellipticine-derived deoxyguanosine adduct from other reactants, deoxyguanosine and 13-hydroxyellipticine, was developed. The structure of this adduct is proposed to correspond to the product formed from ellipticine-13-ylium with the exocyclic 2-NH2 group of guanine in DNA. CONCLUSIONS: The data are the first report on HPLC isolation of the deoxyguanosine adduct formed by 13-hydroxyellipticine in DNA and its partial characterization.

• MeSH
• acetylkoenzym A metabolismus   MeSH
• adukty DNA chemie   izolace a purifikace   MeSH
• arylamin-N-acetyltransferasa metabolismus   MeSH
• arylsulfotransferasa metabolismus   MeSH
• autoradiografie MeSH
• deoxyguanosin chemie   MeSH
• DNA chemie   MeSH
• elipticiny chemie   MeSH
• fosfoadenosinfosfosulfát chemie   MeSH
• indikátory a reagencie MeSH
• izoenzymy metabolismus   MeSH
• katalýza MeSH
• koncentrace vodíkových iontů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 13-hydroxyellipticine MeSH Prohlížeč
• acetylkoenzym A MeSH
• adukty DNA MeSH
• arylamin-N-acetyltransferasa MeSH
• arylsulfotransferasa MeSH
• deoxyguanosin MeSH
• DNA MeSH
• elipticiny MeSH
• fosfoadenosinfosfosulfát MeSH
• indikátory a reagencie MeSH
• izoenzymy MeSH
• N-acetyltransferase 1 MeSH Prohlížeč
• NAT2 protein, human MeSH Prohlížeč
• SULT1A1 protein, human MeSH Prohlížeč
• SULT1A2 protein, human MeSH Prohlížeč

Two compounds known to covalently bind to DNA after their activation with cytochromes P450 (CYPs), carcinogenic benzo(a)pyrene (BaP) and an antineoplastic agent ellipticine, were investigated for their potential to induce CYP and NADPH:CYP reductase (POR) enzymes in rodent livers, the main target organ for DNA adduct formation. Two animal models were used in the study: (i) rats as animals mimicking the fate of ellipticine in humans and (ii) mice, especially wild-type (WT) and hepatic POR null (HRN™) mouse lines. Ellipticine and BaP induce expression of CYP1A enzymes in livers of experimental models, which leads to increase in their enzymatic activity. In addition, both compounds are capable of generating DNA adducts, predominantly in livers of studied organisms. As determined by (32)P postlabelling analysis, levels of ellipticine-derived DNA adducts formed in vivo in the livers of HRN™ mice were reduced (by up to 65%) relative to levels in WT mice, indicating that POR mediated CYP enzyme activity is important for the activation of ellipticine. In contrast to these results, 6.4 fold higher DNA binding of BaP was observed in the livers of HRN™ mice than in WT mice. This finding suggests a detoxication role of CYP1A in BaP metabolism in vivo. In in vitro experiments, DNA adduct formation in calf thymus DNA was up to 25 fold higher in incubations of ellipticine or BaP with microsomes from pretreated animals than with controls. This stimulation effect was attributed to induction of CYP1A1/2 enzymes, which are responsible for oxidative activation of both compounds to the metabolites generating major DNA adducts in vitro. Taken together, these results demonstrate that by inducing CYP1A1/2, ellipticine and BaP modulate their own enzymatic metabolic activation and detoxication, thereby modulating their either pharmacological (ellipticine) and/or genotoxic potential (both compounds).

• Klíčová slova
• HRN™ mice, NADPH:cytochrome P450 reductase, benzo(a)pyrene, cytochromes P450, ellipticine, induction,
• Publikační typ
• časopisecké články MeSH

Ellipticine is an antineoplastic agent, which forms covalent DNA adducts mediated by cytochromes P450 (CYP) and peroxidases. We evaluated the role of hepatic versus extra-hepatic metabolism of ellipticine, using the HRN (Hepatic Cytochrome P450 Reductase Null) mouse model, in which cytochrome P450 oxidoreductase (POR) is deleted in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated i.p. with 1 and 10 mg/kg body weight of ellipticine. Multiple ellipticine-DNA adducts detected by (32)P-postlabelling were observed in organs from both mouse strains. Highest total DNA binding levels were found in liver, followed by lung, kidney, urinary bladder, colon and spleen. Ellipticine-DNA adduct levels in the liver of HRN mice were up to 65% lower relative to WT mice, confirming the importance of CYP enzymes for the activation of ellipticine in livers, recently shown in vitro with human and rat hepatic microsomes. When hepatic microsomes of both mouse strains were incubated with ellipticine, ellipticine-DNA adduct levels with WT microsomes were up to 2.9-fold higher than with those from HRN mice. The ratios of ellipticine-DNA adducts in extra-hepatic organs between HRN and WT mice of up to 4.7 suggest that these organs can activate ellipticine and that more ellipticine is available in the circulation. These results and the DNA adduct patterns found in vitro and in vivo demonstrate that both CYP1A or 3A and peroxidases participate in activation of ellipticine to reactive species forming DNA adducts in the mouse model used in this study.

• MeSH
• adukty DNA analýza   metabolismus   MeSH
• antitumorózní látky metabolismus   toxicita   MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• DNA účinky léků   metabolismus   MeSH
• elipticiny metabolismus   toxicita   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• injekce intraperitoneální MeSH
• izotopové značení metody   MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• játra účinky léků   enzymologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa nedostatek   genetika   metabolismus   MeSH
• radioizotopy fosforu MeSH
• umlčování genů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• antitumorózní látky MeSH
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP3A MeSH
• DNA MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• NADPH-cytochrom c-reduktasa MeSH
• radioizotopy fosforu MeSH

Ellipticine is an antineoplastic agent whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II, and formation of covalent DNA adducts mediated by cytochromes P450 (P450s) and peroxidases. Here, this drug was found to induce CYP1A1 and/or 1A2 enzymes and their enzymatic activities in livers, lungs, and kidneys of rats treated (i.p.) with ellipticine. The induction is transient. In the absence of repeated administration of ellipticine, the levels and activities of the induced CYP1A decreased almost to the basal level 2 weeks after treatment. The ellipticine-mediated CYP1A induction increases the DNA adduct formation by the compound. When microsomal fractions from livers, kidneys, and lungs of rats treated with ellipticine were incubated with ellipticine, DNA adduct formation, measured by (32)P-postlabeling analysis, was up to 3.8-fold higher in incubations with microsomes from pretreated rats than with controls. The observed stimulation of DNA adduct formation by ellipticine was attributed to induction of CYP1A1 and/or 1A2-mediated increase in ellipticine oxidative activation to 13-hydroxy- and 12-hydroxyellipticine, the metabolites generating two major DNA adducts in human and rat livers. In addition to these metabolites, increased formation of the excretion products 9-hydroxy- and 7-hydroxyellipticine was also observed in microsomes of rats treated with ellipticine. Taken together, these results demonstrate for the first time that by inducing CYP1A1/2, ellipticine increases its own metabolism, leading both to an activation of this drug to reactive species-forming DNA adducts and to detoxication metabolites, thereby modulating to some extent its pharmacological and/or genotoxic potential.

• MeSH
• adukty DNA MeSH
• antitumorózní látky farmakologie   MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• cytochrom P-450 CYP1A2 biosyntéza   genetika   MeSH
• cytochromy MeSH
• elipticiny farmakologie   MeSH
• enzymová indukce účinky léků   MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• mikrozomy enzymologie   MeSH
• plíce účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adukty DNA MeSH
• antitumorózní látky MeSH
• Cyp1a2 protein, rat MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• cytochromy MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• messenger RNA MeSH

OBJECTIVES: Ellipticine is a potent antineoplastic agent exhibiting multiple action mechanisms. Recently, we found that after cytochrome P450 (CYP)-mediated oxidation ellipticine forms covalent DNA adducts. Ellipticine oxidation by isolated CYP and its binding to DNA is the target of this study. METHODS: High performance liquid chromatography (HPLC) was employed for separation and characterization of ellipticine metabolites generated by CYPs. The (32)P-postlabeling technique was utilized to determine ellipticine-DNA adducts. RESULTS: Purified CYP enzymes reconstituted with NADPH:CYP reductase oxidized ellipticine to up to five metabolites, 7-hydroxy-, 9-hydroxy-, 12-hydroxy-, 13-hydroxyellipticine and ellipticine N(2)-oxide. However, only CYP1A1 was capable to form all metabolites. Using the reconstituted enzymatic system, we demonstrated that the detoxication ellipticine metabolites, 7-hydroxyellipticine and 9-hydroxyellipticine, are mainly generated by CYP1A1 and 1A2, while those responsible for DNA binding, 13-hydroxy-, 12-hydroxyellipticine and ellipticine N(2)-oxide, by CYP3A1 and 2C3. Likewise, the most efficient CYPs forming DNA adducts from ellipticine were CYP3A1 and 2C3. CONCLUSIONS: The results showed that the system of purified CYPs reconstituted with NADPH: CYP reductase proved for ellipticine oxidation provide a true reflection of the situation in the microsomal membrane.

• MeSH
• adukty DNA metabolismus   MeSH
• antitumorózní látky farmakokinetika   MeSH
• biologické modely MeSH
• elipticiny farmakokinetika   MeSH
• I. fáze biotransformace * MeSH
• jaterní mikrozomy chemie   metabolismus   MeSH
• králíci MeSH
• krysa rodu Rattus MeSH
• NADP chemie   metabolismus   MeSH
• NADPH-cytochrom c-reduktasa izolace a purifikace   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 chemie   izolace a purifikace   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• antitumorózní látky MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• NADP MeSH
• NADPH-cytochrom c-reduktasa MeSH
• systém (enzymů) cytochromů P-450 MeSH