scholarly journals Cytochrome P450-mediated metabolism of N-(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogens o-anisidine and o-nitroanisole

2008 ◽  
Vol 1 (3-4) ◽  
pp. 218-224 ◽  
Author(s):  
Karel Naiman ◽  
Helena Dračínská ◽  
Martin Dračínský ◽  
Markéta Martínková ◽  
Václav Martínek ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochromes P450 ◽  
Environmental Pollutants ◽  
Human Metabolite ◽  
Hepatic Microsomes ◽  
Minor Metabolite ◽  
Reactive Compound ◽  
A Minor

Cytochrome P450-mediated metabolism ofN-(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogenso-anisidine ando-nitroanisoleN-(2-methoxyphenyl)hydroxylamine is a human metabolite of the industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole). Here, we investigated the ability of hepatic microsomes from rat and rabbit to metabolize this reactive compound. We found thatN-(2-methoxyphenyl)hydroxylamine is metabolized by microsomes of both species mainly too-aminophenol and a parent carcinogen,o-anisidine, whereas 2-methoxynitrosobenzene (o-nitrosoanisole) is formed as a minor metabolite. AnotherN-(2-methoxyphenyl)hydroxylamine metabolite, the exact structure of which has not been identified as yet, was generated by hepatic microsomes of rabbits, but its formation by those of rats was negligible. To evaluate the role of rat hepatic microsomal cytochromes P450 (CYP) inN-(2-methoxyphenyl)hydroxylamine metabolism, we investigated the modulation of its metabolism by specific inducers of these enzymes. The results of this study show that rat hepatic CYPs of a 1A subfamily and, to a lesser extent those of a 2B subfamily, catalyzeN-(2-methoxyphenyl)hydroxylamine conversion to form both its reductive metabolite,o-anisidine, ando-aminophenol. CYP2E1 is the most efficient enzyme catalyzing conversion ofN-(2-methoxyphenyl)hydroxylamine too-aminophenol.

scholarly journals Rat cytochromes P450 oxidize 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone

2008 ◽  
Vol 1 (2) ◽  
pp. 150-154 ◽  
Author(s):  
Jana Mizerovská ◽  
Helena Dračínská ◽  
Volker Arlt ◽  
Jiří Hudeček ◽  
Petr Hodek ◽  
...  
Keyword(s):  
High Performance ◽  
Cytochromes P450 ◽  
Liver Microsomes ◽  
Metabolic Activation ◽  
Environmental Pollutant ◽  
Human Metabolite ◽  
Cyp Enzymes ◽  
Hepatic Microsomes ◽  
Oxidative Metabolites

Rat cytochromes P450 oxidize 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone3-Aminobenzanthrone (3-ABA) is a human metabolite of carcinogenic 3-nitrobenzanthrone (3-NBA), which occurs in diesel exhaust and air pollution. Understanding which cytochrome P450 (CYP) enzymes are involved in metabolic activation and/or detoxication of this toxicant is important in the assessment of an individual's susceptibility to this substance. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 3-ABA and to examine the metabolites formed during such an oxidation. The metabolites formed by CYPs in rat hepatic microsomes were separated by high performance liquid chromatography (HPLC). 3-ABA is oxidized by these enzymes to three metabolites, which were separated by HPLC as distinguish product peaks. Using co-chromatography with synthetic standards, two of them were identified to be oxidative metabolites of 3-ABA,N-hydroxy-3-ABA and 3-NBA. The structure of another 3-ABA metabolite remains to be characterized. To define the role of rat hepatic CYP enzymes in metabolism of 3-ABA, we investigated the modulation of its oxidation using different inducers of CYPs for treatment of rats to enrich the liver microsomes with individual CYPs. Based on these studies, we attribute most of 3-ABA oxidation in rat hepatic microsomes to CYP2B, followed by CYP1A, although a role of other hepatic CYPs cannot be ruled out. Inhibition of 3-ABA oxidation by selective inhibitors of individual CYPs, supported this finding.

Rat liver microsomal metabolism of o-aminophenol and N-(2-methoxyphenyl)hydroxylamine, two metabolites of the environmental pollutant and carcinogen o-anisidine in humans

2010 ◽  
Vol 75 (12) ◽  
pp. 1229-1247 ◽  
Author(s):  
Karel Naiman ◽  
Petr Hodek ◽  
Jiří Liberda ◽  
Heinz H. Schmeiser ◽  
Eva Frei ◽  
...  
Keyword(s):  
Rat Liver ◽  
Dna Adducts ◽  
Cytochromes P450 ◽  
Environmental Pollutant ◽  
Microsomal Metabolism ◽  
Human Metabolite ◽  
Hepatic Microsomes

o-Aminophenol and N-(2-methoxyphenyl)hydroxylamine are human metabolites of the industrial and environmental pollutant and bladder carcinogen 2-methoxyaniline (o-anisidine). The latter one is also a human metabolite of another pollutant and bladder carcinogen, 2-methoxynitrobenzene (o-nitroanisole). Here, we investigated the ability of rat hepatic micro- somes to metabolize these metabolites. N-(2-methoxyphenyl)hydroxylamine is metabolized by rat hepatic microsomes to o-aminophenol and predominantly o-anisidine, the parent carcinogen from which N-(2-methoxyphenyl)hydroxylamine is formed. In addition, two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, were generated. On the contrary, no metabolites were found to be formed from o-aminophenol by rat hepatic microsomes. Whereas N-(2-methoxyphenyl)hydroxylamine is responsible for formation of three deoxyguanosine adducts in DNA, o-aminophenol seems to be a detoxication metabolite of N-(2-methoxyphenyl)hydroxylamine and/or a parental carcinogen, o-anisidine; no o-aminophenol-derived DNA adducts were found after its reaction with microsomal cytochromes P450 and peroxidases.

scholarly journals Interaction of prostacyclin synthase with cytochromes P450

2019 ◽  
Vol 65 (1) ◽  
pp. 63-66
Author(s):  
O.V. Gnedenko ◽  
E.O. Yablokov ◽  
P.V. Ershov ◽  
A.V. Svirid ◽  
T.V. Shkel ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Essential Role ◽  
Protein Complexes ◽  
Cytochromes P450 ◽  
Thromboxane A2 ◽  
Cytochrome P450s ◽  
Cytochrome P450 Monooxygenase ◽  
P450 Monooxygenase ◽  
Prostacyclin Synthase

Biosensor experiments on investigation of interaction between prostacyclin synthase (PGIS) and different proteins of the cytochrome P450 monooxygenase systems were perfomed. Interaction of PGIS with microsomal (CYP21A2, CYP2E1) and mitochondrial (CYP27A1, CYP11B1, CYP11B2, CYP11A1) cytochrome P450s was detected. Kinetic and equilibrium parameters of protein complexes formation were determined. Data obtained suggest an essential role of these hemoproteins interaction in regulation of prostacyclin and thromboxane A2 biosynthesis.

scholarly journals Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants

1993 ◽  
Vol 90 (23) ◽  
pp. 11147-11151 ◽  
Author(s):  
O G Khatsenko ◽  
S S Gross ◽  
A B Rifkind ◽  
J R Vane
Keyword(s):  
Nitric Oxide ◽  
Cytochrome P450 ◽  
Nitric Oxide Synthase ◽  
Cytochromes P450 ◽  
Hepatic Metabolism ◽  
Spectral Studies ◽  
Rat Liver Microsomes ◽  
Hepatic Microsomes ◽  
Oxide Synthase

Bacterial lipopolysaccharide (LPS) and a diverse array of other immunostimulants and cytokines suppress the metabolism of endogenous and exogenous substances by reducing activity of the hepatic cytochrome P450 mixed-function oxidase system. Although this effect of immunostimulants was first described almost 40 yr ago, the mechanism is obscure. Immunostimulants are now known to cause NO overproduction by cells via induction of nitric oxide synthase. We have investigated whether NO overproduction is involved in suppressing hepatic metabolism by LPS. In vitro treatment of hepatic microsomes with NO, produced by chemical decomposition of 3-morpholinosydnonimine or by nitric oxide synthase, substantially suppressed cytochrome P450-dependent oxygenation reactions. This effect of NO was seen with hepatic microsomes prepared from two species (rat and chicken) and after exposure to chemicals that induce distinct molecular isoforms of cytochromes P450 (beta-naphthoflavone, 3-methylcholanthrene, and phenobarbital). Spectral studies indicate that NO reacts in vitro with both Fe(2+)- and Fe(3+)-hemes in microsomal cytochromes P450. In vivo, LPS diminished the phenobarbital-induced dealkylation of 7-pentoxyresorufin by rat liver microsomes and reduced the apparent P450 content as measured by CO binding. These LPS effects were associated with induction of NO synthesis; LPS-induced NO synthesis showed a strong positive correlation with the severity of cytochrome P450 inhibition. The decrease in both hepatic microsomal P450 activity and CO binding caused by LPS was largely prevented by the selective NO synthase inhibitor N omega-nitro-L-arginine methyl ester. Our findings implicate NO over-production as a major factor mediating the suppression of hepatic metabolism by immunostimulants such as LPS.

scholarly journals Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation

2019 ◽  
Vol 20 (14) ◽  
pp. 3392 ◽  
Author(s):  
Radek Indra ◽  
Petr Pompach ◽  
Václav Martínek ◽  
Paulína Takácsová ◽  
Katarína Vavrová ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Active Center ◽  
High Efficiency ◽  
Kinase Inhibitor ◽  
Cytochromes P450 ◽  
Cytochrome B5 ◽  
Cancer Drug ◽  
Hepatic Microsomes ◽  
Kinetics Of

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to N-desmethylvandetanib and vandetanib-N-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b5 stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 N-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center.

Urinary selenium concentrations

1993 ◽  
Vol 39 (10) ◽  
pp. 2040-2052 ◽  
Author(s):  
M Sanz Alaejos ◽  
C Díaz Romero
Keyword(s):  
Women Workers ◽  
Control Groups ◽  
Dietary Selenium ◽  
Pathological Conditions ◽  
Wide Range ◽  
Minor Metabolite ◽  
Excretion Rates ◽  
A Minor ◽  
Lower Urinary

Abstract Urinary selenium concentrations are used as an indicator of selenium status. A strong correlation has been established between dietary selenium and daily urinary selenium excretion in a wide range of populations from all over the world with different dietary selenium intake. Data on urinary selenium concentrations in healthy individuals and patients with different pathological conditions are reviewed. Selenium excretion rates of 20-200 micrograms/day are not associated with deficiency or toxicity problems. Urinary Se excretion is decreased in children, elderly people, and pregnant women. Workers exposed to heavy metals, and cancer patients, have higher and lower urinary Se concentrations, respectively, than control groups. The trimethylselenonium ion, a minor metabolite of Se in urine, assumes a significant role only in the detoxification of excess Se intake. Studies of bioavailability and balance show the important role of the kidneys in homeostatic regulation of Se.

Metabolism of Carcinogenic Azo Dye Sudan I by Rat, Rabbit, Minipig and Human Hepatic Microsomes

2002 ◽  
Vol 67 (12) ◽  
pp. 1883-1898 ◽  
Author(s):  
Václav Martínek ◽  
Marie Stiborová
Keyword(s):  
Cytochromes P450 ◽  
Human Health Risk ◽  
Enzymatic System ◽  
Cytochrome P450 1A1 ◽  
Predominant Role ◽  
Hepatic Microsomes ◽  
Sudan I ◽  
Microsomal Enzymatic System

We investigated the ability of hepatic microsomal samples from different species including human to metabolize rodent carcinogen Sudan I (C.I. Solvent Yellow 14, 1-(phenylazo)-2-naphthol). A comparison between experimental animals and the human microsomal enzymatic system is essential for the extrapolation of animal carcinogenicity data to assess human health risk. Major metabolites produced from Sudan I by microsomes of all species were C-hydroxylated derivatives identified as 1-[(4-hydroxyphenyl)azo]-2-naphthol and 1-(phenylazo)naphthalene-2,6-diol. Additional minor C-hydroxylated products of Sudan I oxidation were 1-[(4-hydroxyphenyl)azo]naphthalene-2,6-diol and 1-[(3,4-dihydroxyphenyl)- azo]-2-naphthol. Human microsomes generated the pattern of Sudan I metabolites reproducing that formed by hepatic microsomes of rats. While microsomes of rabbit and minipig favored the production of the metabolite hydroxylated in position 6 of the naphthol ring of the Sudan I molecule, those of human and rat predominantly produced 1-[(4-hydroxyphenyl)azo]-2-naphthol. Therefore, rat microsomes are a suitable in vitro system mimicking the metabolism of Sudan I in humans. To define the role of specific cytochromes P450 in the Sudan I metabolism by rat microsomes, we investigated the modulation of Sudan I oxidation by specific inducers and selective inhibitors of these enzymes. The results suggest that cytochromes P450 1A1 and 3A are responsible for Sudan I metabolism by rat microsomes. Using purified enzymes, their ability to oxidize Sudan I was confirmed. The data clearly demonstrate the predominant role of cytochrome P450 1A1 in the Sudan I metabolism and suggest a carcinogenic potency of this rodent carcinogen for humans.

scholarly journals Oxidation of carcinogenic 2-nitroanisole by rat cytochromes P450 - similarity between human and rat enzymes

2008 ◽  
Vol 1 (2) ◽  
pp. 182-185 ◽  
Author(s):  
Martina Svobodová ◽  
Helena Dračínská ◽  
Markéta Martínková ◽  
Jiří Hudeček ◽  
Petr Hodek ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Insect Cells ◽  
Cytochromes P450 ◽  
Major Metabolite ◽  
Environmental Carcinogen ◽  
Cyp Enzymes ◽  
Hepatic Microsomes ◽  
Potent Carcinogen

Oxidation of carcinogenic 2-nitroanisole by rat cytochromes P450 - similarity between human and rat enzymes2-Nitroanisole (2-NA) is an important industrial pollutant and a potent carcinogen for rodents. Understanding which cytochrome P450 (CYP) enzymes are involved in its metabolism are important to assess an individual's susceptibility to this environmental carcinogen. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 2-NA, to examine the metabolites formed during such an oxidation, and to compare such efficiencies of rat CYPs with those of human. 2-NA is oxidized by rat hepatic microsomes to 2-nitrophenol (2-NP) as the major metabolite, and to 2,6-dihydroxynitrobenzene (2,6-DNB) and 2,5-dihydroxynitrobenzene (2,5-DNB) as the minor products. All these metabolites are suggested as detoxication products. Using hepatic microsomes of rats pre-treated with specific CYP inducers and microsomes from Baculovirus transfected insect cells expressing recombinant rat and human CYP enzymes we found that rat recombinant CYP2E1, 2D2, 2B2, 2C6 and 1A1, as well as orthologous human CYP enzymes are the most efficient enzymes metabolizing 2-NA. However, human CYP1A1 oxidize 2-NA with a higher efficiency than the enzyme of rats. The results show the participation of orthologous CYPs in 2-NA oxidation by both species and underline the suitability of rat species as a model to evaluate human susceptibility to 2-NA.

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