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 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.

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 Properties of cytosolic components activating rat hepatic 5-deiodination in the presence of NADPH

1986 ◽  
Vol 234 (2) ◽  
pp. 391-398 ◽  
Author(s):  
K Sawada ◽  
B C W Hummel ◽  
P G Walfish
Keyword(s):  
Enzyme Activity ◽  
Glutathione Reductase ◽  
Rat Liver ◽  
Column Chromatography ◽  
Reduced Glutathione ◽  
Hydrogen Acceptor ◽  
Simultaneous Addition ◽  
Heat Stable ◽  
Hepatic Microsomes ◽  
Normal Rat

The effects of cytosol, NADPH and reduced glutathione (GSH) on the activity of 5′-deiodinase were studied by using washed hepatic microsomes from normal fed rats. Cytosol alone had little stimulatory effect on the activation of microsomal 5′-deiodinase. NADPH had no stimulatory effect on the microsomal 5′-deiodinase unless cytosol was added. 5′-deiodinase activity was greatly enhanced by the simultaneous addition of NADPH and cytosol (P less than 0.001); this was significantly higher than that with either NADPH or cytosol alone (P less than 0.001). GSH was active in stimulating the enzyme activity in the absence of cytosol, but the activity of 5′-deiodinase with 62 microM-NADPH in the presence of cytosol was significantly higher than that with 250 microM-GSH in the presence of the same concentration of cytosol (P less than 0.001). The properties of the cytosolic components essential for the NADPH-dependent activation of microsomal 5′-deiodinase independent of a glutathione/glutathione reductase system were further assessed using Sephadex G-50 column chromatography to yield three cytosolic fractions (A, B and C), wherein A represents pooled fractions near the void volume, B pooled fractions of intermediate Mr (approx. 13 000), and C of low Mr (approx. 300) containing glutathione. In the presence of NADPH (1 mM), the 5′-deiodination rate by hepatic washed microsomes is greatly increased if both A and B are added and is a function of the concentrations of A, B, washed microsomes and NADPH. A is heat-labile, whereas B is heat-stable and non-dialysable. These observations provide the first evidence of an NADPH-dependent cytosolic reductase system not involving glutathione which stimulates microsomal 5′-deiodinase of normal rat liver. The present data are consistent with a deiodination mechanism involving mediation by a reductase (other than glutathione reductase) in fraction A of an NADPH-dependent reduction of a hydrogen acceptor in fraction B, followed by reduction of oxidized microsomal deiodinase by the reduced acceptor (component in fraction B).

Immimological titration of 3-N-acetyl-hydroxyamino-4, 6-dimethyldipyrido(l, 2-a: 3', 2'-d)imidazole-rat liver DNA adducts

1985 ◽  
Vol 6 (6) ◽  
pp. 937-939 ◽  
Author(s):  
Eric Hebert ◽  
Germain Saint-Ruf ◽  
Marc Leng
Keyword(s):  
Rat Liver ◽  
Dna Adducts

scholarly journals Monitoring by HPLC of Chamomile Flavonoids Exposed to Rat Liver Microsomal Metabolism

2009 ◽  
Vol 3 ◽  
pp. 1-7 ◽  
Author(s):  
Georg Petroianu ◽  
Éva Szőke ◽  
Huba Kalász ◽  
Péter Szegi ◽  
Rudolf Laufer ◽  
...  
Keyword(s):  
Rat Liver ◽  
Microsomal Metabolism

Induction of cytochromes P450 2B and 2E1 in rat liver by isomeric picoline N-oxides

1997 ◽  
Vol 93 (2-3) ◽  
pp. 195-203 ◽  
Author(s):  
Michael Murray ◽  
Rachel M Sefton ◽  
Robert Martini ◽  
Alison M Butler
Keyword(s):  
Rat Liver ◽  
Cytochromes P450

scholarly journals Effects of clofibrate on some microsomal hydroxylations involved in the formation and metabolism of bile acids in rat liver

1976 ◽  
Vol 156 (2) ◽  
pp. 445-448 ◽  
Author(s):  
B O Angelin ◽  
I Björkhem ◽  
K Einarsson
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Rat Liver ◽  
Lithocholic Acid ◽  
Present Knowledge ◽  
Acid Formation ◽  
Microsomal Metabolism ◽  
Endogenous Cholesterol

1. The liver microsomal metabolism of [4-14C]cholesterol, endogenous cholesterol, 7 α-hydroxy-4-[6 β-3H]cholesten-3-one, 5-β-[7 β-3H]cholestane-3 α, 7 α-diol and [3H]lithocholic acid was studdied in control and clofibrate (ethyl p-chlorophenoxyisobutyrate)-treated rats. 2. The extent of 7 α-hydroxylation of exogenous [414C]cholesterol and endogenous cholesterol, the latter determined with a mass fragmentographic technique, was the same in the two groups of rats. The extent of 12 α-hydroxylation of 7 α-hydroxy-4-cholesten-3-one and 5 β-cholestane-3 α, 7 α-diol was increased by about 60 and 120% respectively by clofibrate treatment. The 26-hydroxylation of 5 β-cholestane-3 α, 7 α-diol was not significantly affected by clofibrate. The 6 β-hydroxylation of lithocholic acid was about 80% higher in the clofibrate-treated animals than in the controls. 3. The results are discussed in the context of present knowledge about the liver microsomal hydroxylating system and bile acid formation in patients with hypercholesterolaemia, treated with clofibrate.

scholarly journals Further Evidence on the Intramolecular Lactonization in Rat Liver Microsomal Metabolism of 12-O-acetylated Retronecine-type Pyrrolizidine Alkaloids

2013 ◽  
Vol 8 (11) ◽  
pp. 1934578X1300801 ◽  
Author(s):  
Jun Tang ◽  
Zhengtao Wang ◽  
Teruaki Akao ◽  
Masao Hattori
Keyword(s):  
Physical Properties ◽  
Spectral Data ◽  
Rat Liver ◽  
Pyrrolizidine Alkaloids ◽  
Pyrrolizidine Alkaloid ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Microsomal Metabolism ◽  
Chromatographic Methods ◽  
Transformation Pathway

We have previously found evidence of intramolecular lactonization in rat liver microsomal metabolism of isoline, a 12- O-acetylated pyrrolizidine alkaloid. In this study, the metabolism of another 12- O-acetylated pyrrolizidine alkaloid, acetylduciformine, by the proposed transformation pathway was investigated under the same incubation conditions. Two deacetylated metabolites from acetylduciformine were isolated and purified by chromatographic methods, and further characterized based on their physical properties and spectral data. One metabolite (lankongensisine A) was the lactone of another one (duciformine). Both compounds were first obtained as hydrolyzed metabolites from acetylduciformine by rat liver microsomes. More importantly, the present study provided further evidence for the intramolecular lactonization in the microsomal metabolism of 12- O-acetylated retronecine-type PAs.

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