Metabolic Activation of<i>N</i>-Hydroxy Compounds by Conjugation

Irving, Charles C.

doi:10.3109/00498257109041505

Cited by 55 publications

(12 citation statements)

References 20 publications

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“…The main products are the relatively stable glucuronides and the more labile sulfate conjugates of the N-hydroxy group (2)(3)(4). Since the spontaneous breakdown of the N, O-glucuronides is much slower than that of the N,O-sulfonates, the chemical mechanisms of breakdown of these conjugates can more easily be studied with the N, O-glucuronides.…”

Section: Introductionmentioning

confidence: 99%

“…The sulfate conjugates are very prone to rapid, spontaneous rearrangements and, in general, are very labile in aqueous media, even at pH 7 (2,5). However, the more *Department of Pharmacology, State University of Groningen, Groningen, The Netherlands stable glucuronide conjugate of N-hydroxy-2-acetylaminofluorene W-hydroxy-2-AAF) can be isolated, and the properties of the reactive intermediate formed during its breakdown have been studied in vitro (2,3). Similarly, the breakdown products of the glucuronide conjugate of N-hydroxyphenacetin could be characterized completely (5).…”

Section: Introductionmentioning

confidence: 99%

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Sulfation and Glucuronidation as Competing Pathways in the Metabolism of Hydroxamic Acids: The Role of N,O-Sulfonation in Chemical Carcinogenesis of Aromatic Amines

Mulder¹,

Meerman²

1983

Environmental Health Perspectives

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Aromatic amines can be metabolized by N-acetylation and N-hydroxylation to hydroxamic acids; these subsequently are conjugated to form the N,O-sulfonate and N,O-glucuronide conjugates. The N,O-sulfonates are highly labile metabolites that generate reactive intermediates involved in the covalent binding of the parent compound to protein, RNA and DNA, as well as to low molecular compounds like glutathione. This paper discusses methods used to decrease sulfation in vivo, and thereby to enhance the formation of the more stable N,O-glucuronides from N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylamino-4'-fluorobiphenyl. Acetaminophen pretreatment decreases the sulfate availability, but results in many side effects that complicate the analysis of the results. An 8% casein diet reduces the sulfate availability in the rat to approximately 20% of control and thus offers an effective approach to decrease sulfation.The most effective selective inhibition of sulfation is by pentachlorophenol, which very strongly reduces N,O-sulfonation of both hydroxamic acids, and selectively inhibits the formation of DNA adducts that have retained the N-acetyl group. This inhibitor and the related 2,6-dichloro-4-nitrophenol can be employed to study the role of sulfation of hydroxamic acids in initiation and promotion of tumor formation by aromatic amines.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sulfation and Glucuronidation as Competing Pathways in the Metabolism of Hydroxamic Acids: The Role of N,O-Sulfonation in Chemical Carcinogenesis of Aromatic Amines

Mulder¹,

Meerman²

1983

Environmental Health Perspectives

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“…These observations were confirmed by HPLC which showed the presence of one major adduct, dG-8-AF, after 28 days on 0.02% 2-AAF and also after a subsequent 28 days on the control diet. Since Irving has demonstrated a decrease in rat liver sulfotransferase with 2 weeks of 2-AAF feeding (21), it was not unexpected to find that neither dG-8-AAF or dG-N2-AAF were formed in rat liver DNA at this time. Thus it would appear that accumulation of dG-8-AF may be the most persistent sequela of chronic 2-AAF feeding where effects on DNA are concerned.…”

Section: Discussionmentioning

confidence: 99%

Determination of 2-Acetylaminofluorene Adducts by Immunoassay

Poirier¹,

True²,

Laishes³

1983

Environmental Health Perspectives

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Antisera elicited in rabbits were used in radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) to determine femtomole quantities of deoxyguanosin-8-yl-acetylaminofluorene (dg-8-AAF) and deoxyguanosin-8-yl-aminofluorene (dg-8-AF). These adducts have been monitored in liver and kidney DNA of male Wistar-Furth rats fed 0.02% or 0.04% 2-acetylaminofluorene (2-AAF) either continuously or for a limited time followed by an interval on control diet. After 24 hr of 0.02% 2-AAF feeding, substantial levels of binding (80 fmole/4g DNA) were observed in liver DNA and increased with time, reaching a plateau of approximately 230 fmole/,Ag DNA at 30 days and thereafter. During the first week of continuous feeding about 80% of the total C-8 adducts in the liver DNA were deacetylated (dG-8-AF). By 25-60 days, dG-8-AF represented 97-100% of all C-8 adducts as measured by RIA and confirmed by HPLC. Values for C-8 adduct formation in kidney DNA were severalfold lower than in liver and dG-8-AF represented >90% of C-8 adducts at all times studied.In removal or repair experiments, rats were fed 2-AAF for 3, 7 or 28 days, the 2-AAF diet was discontinued and the liver adducts assayed after intervals on control diet. When dietary 2-AAF administration was for 3 or 7 days, removal of adducts was efficient and almost complete by 28 days on control diet, with preferential retention of dG-8-AF. However, when dietary 2-AAF administration was for 28 days, adduct levels were higher, the repair capacity was saturated and the removal of C-8 adducts was not complete after control diet for a 28-day interval. In a preliminary experiment when[3H]-2-AAF was fed for 3 days, after 25 days of 0.02% 2-AAF, the rates of newly formed adduct formation and removal were similar to those observed for the initial 3 days of 2-AAF feeding. These results demonstrate the predominance and persistence of dG-8-AF in liver and kidney DNA of 2-AAFfed rats and suggest that the repair capacity of the whole rat liver was not diminished after 1 month of 2-AAF feeding.

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“…However, interferences can occur. Gas-chromatographic separations of these compounds have already been reported (Irving, 1971;Razzouk et al, 1978;Batardy-Gregoire et al, 1982;Neelakantan et al, 1986). This paper deals with a new type of silylated derivatives of 2-AAF and its metabolites, the tert.-butyldimethylsilyl (tBDMS) compounds.…”

Section: Introductionmentioning

confidence: 99%

Gas chromatography-mass spectrometry analysis of tert.-butyldimethylsilyl derivatives of 2-acetylaminofluorene and metabolites in isolated rat hepatocytes

et al. 1987

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A new technique for the conversion of 2-acetylaminofluorene and several ring-hydroxylated metabolites to mono- and di-tert.-butyldimethylsilyl derivatives was developed to permit their analysis by gas chromatography-mass spectrometry in order to quantify the metabolism of 2-acetylaminofluorene incubated in freshly isolated rat hepatocytes. This new gas chromatography-mass spectrometry method allowed the separation, identification and quantitation of seven known metabolites comprising five arylhydroxylated compounds, 2-aminofluorene and N-hydroxy-2-acetylaminofluorene.

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Metabolic Activation ofN-Hydroxy Compounds by Conjugation

Cited by 55 publications

References 20 publications

Sulfation and Glucuronidation as Competing Pathways in the Metabolism of Hydroxamic Acids: The Role of N,O-Sulfonation in Chemical Carcinogenesis of Aromatic Amines

Sulfation and Glucuronidation as Competing Pathways in the Metabolism of Hydroxamic Acids: The Role of N,O-Sulfonation in Chemical Carcinogenesis of Aromatic Amines

Determination of 2-Acetylaminofluorene Adducts by Immunoassay

Gas chromatography-mass spectrometry analysis of tert.-butyldimethylsilyl derivatives of 2-acetylaminofluorene and metabolites in isolated rat hepatocytes

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