729. The preparation of o-aminophenyl sulphates

Boyland, E.; Manson, D.; Sims, P.

doi:10.1039/jr9530003623

Cited by 67 publications

(53 citation statements)

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“…32 The mixture was placed in a thermomixer at 37 °C and agitated at 650 rpm for two h before neutralization with 1N HCl. The products were purified via the Agilent 1260 Infinity HPLC system and chromatographic conditions as described above for 3-HO-AαC.…”

Section: Methodsmentioning

confidence: 99%

Measurement of the Heterocyclic Amines 2-Amino-9H-pyrido[2,3-b]indole and 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Urine: Effects of Cigarette Smoking

Konorev

Koopmeiners

Tang

et al. 2015

Chem. Res. Toxicol.

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2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAAs) formed during the combustion of tobacco and during the high-temperature cooking of meats. Human enzymes biotransform AαC and PhIP into reactive metabolites, which can bind to DNA and lead to mutations. We sought to understand the relative contribution of smoking and diet to the exposure of AαC and PhIP, by determining levels of AαC, its ring-oxidized conjugate 2-amino-9H-pyrido[2,3-b]indole-3-yl sulfate (AαC-3-OSO3H), and PhIP in urine of smokers on a free-choice diet before and after a six week tobacco smoking cessation study. AαC and AαC-3-OSO3H were detected in more than 90% of the urine samples of all subjects during the smoking phase. The geometric mean levels of urinary AαC during the smoking and cessation phases were 24.3 pg/mg creatinine and 3.2 pg/mg creatinine, and the geometric mean levels of AαC-3-OSO3H were 47.3 pg/mg creatinine and 3.7 pg/mg creatinine. These decreases in the mean levels of AαC and AαC-3-OSO3H were, respectively, 87% and 92%, after the cessation of tobacco (P < 0.0007). However, PhIP was detected in < 10% of the urine samples, and the exposure to PhIP was not correlated to smoking. Epidemiological studies have reported that smoking is a risk factor for cancer of the liver and gastrointestinal tract. It is noteworthy that AαC is a hepatocellular carcinogen and induces aberrant crypt foci, early biomarkers of colon cancer, in rodents. Our urinary biomarker data demonstrate that tobacco smoking is a significant source of AαC exposure. Further studies are warranted to examine the potential role of AαC as a risk factor for hepatocellular and gastrointestinal cancer in smokers.

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Section: Methodsmentioning

confidence: 99%

Measurement of the Heterocyclic Amines 2-Amino-9H-pyrido[2,3-b]indole and 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Urine: Effects of Cigarette Smoking

Konorev

Koopmeiners

Tang

et al. 2015

Chem. Res. Toxicol.

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“…31 2-Amino-9 H -pyrido[2,3- b ]indol-3-yl sulfate (AαC-3-OSO 3 H) and [ 13 C 6 ] AαC-3-OSO 3 H were prepared by the Boyland-Sims oxidation of AαC with potassium persulfate. 32 N 2 -(β-1-Glucosidurony1)-2-amino-9 H -pyrido[2,3- b ]indole (AαC- N 2 -Glu) was prepared with human liver microsomes fortified with UDPGA as previously reported. 33 dG-C8-AαC and the isotopically labeled [ 13 C 10 ]-dG-C8-AαC were synthesized as described.…”

Section: Methodsmentioning

confidence: 99%

Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice

Turesky

Konorev

Fan

et al. 2015

Chem. Res. Toxicol.

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2-Amino-9H-pyrido[2,3-b]indole (AαC), a carcinogen formed during the combustion of tobacco and cooking of meat, undergoes cytochrome P450 (P450) metabolism to form the DNA adduct N-(deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AαC). We evaluated the roles of P450 expressed in the liver and intestine to bioactivate AαC by employing male B6 wild-type (WT) mice, liver-specific P450 reductase (Cpr)-null (LCN) mice, and intestinal epithelium-specific Cpr-null (IECN) mice. Pharmacokinetic parameters were determined for AαC, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AαC-3-OSO3H), and N2-(β-1-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N2-Glu) with animals dosed by gavage with AαC (13.6 mg/kg). The uptake of AαC was rapid with no difference in the plasma half-lives (t1/2) of AαC, AαC-3-OSO3H and AαC-N2-Glu among mouse models. The maximal plasma concentrations (Cmax) and the areas under concentration-time curve (AUC0-24h) of AαC and AαC-N2-Glu were 4-24 fold higher in LCN than in WT mice, but were not different between WT and IECN mice. These findings are consistent with the ablation of hepatic P450 activity in LCN mice. However, the Cmax and AUC0-24h of AαC-3-OSO3H in plasma were not substantially different among the mouse models. Similar pharmacokinetic parameters were obtained with WT and LCN mice treated with a lower AαC dose (1.36 mg/kg). dG-C8-AαC was detected at similar levels in the livers of all three mouse models at the high AαC dose; levels of dG-C8-AαC in colon, bladder, and lung were greater in LCN than in WT mice and were the same in colon of IECN and WT mice. At the low AαC dose, dG-C8-AαC occurred at ~40% lower levels in liver of LCN mouse than in WT mouse liver, but adduct levels remained higher in extrahepatic tissues of LCN mice. Therefore, hepatic P450 plays an important role in detoxication of AαC, but other hepatic enzyme(s) contributes to the bioactivation of AαC. P450s expressed in the intestine do not appreciably contribute to bioactivation of AαC in mice.

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“…was purchased from BDH as the sulphate dimer (Metol). N-Methyl-2-aminophenol was prepared using the method of Boyland and Sims (24,25) as fawn crystals, with a m.p. of 92-94°C.…”

Section: Methodsmentioning

confidence: 99%

The in vitro metabolism of N,N-dimethylaniline by guinea pig and rabbit tissue preparations

Gorrod

Gooderham

1981

European Journal of Drug Metabolism and Pharmacokinetics

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A study of the in vitro metabolism of N,N-dimethylaniline using guinea pig and rabbit preparations and GLC techniques has confirmed N-demethylation and N-oxidation and established ring hydroxylation as metabolic routes. Whereas N-demethylation and N-oxidation are major routes of metabolism, ring hydroxylation is a comparatively minor pathway. Like N-demethylase and N-oxidase, the 4-hydroxylase has been shown to be a microsomal enzyme. The major ring hydroxylated product of N,N-dimethylaniline is N,N-dimethyl-4-aminophenol; N-methyl-4-aminophenol is subsequently formed. The apparent Km and V max values for N-demethylation, N-oxidation and 4-hydroxylation, are presented for both the guinea pig and the rabbit.

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729. The preparation of o-aminophenyl sulphates

Cited by 67 publications

References 0 publications

Measurement of the Heterocyclic Amines 2-Amino-9H-pyrido[2,3-b]indole and 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Urine: Effects of Cigarette Smoking

Measurement of the Heterocyclic Amines 2-Amino-9H-pyrido[2,3-b]indole and 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Urine: Effects of Cigarette Smoking

Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice

The in vitro metabolism of N,N-dimethylaniline by guinea pig and rabbit tissue preparations

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