Conjugates of N-Hydroxy Compounds

Irving, Charles C.

doi:10.1016/b978-0-12-257601-0.50009-8

Cited by 25 publications

(17 citation statements)

References 86 publications

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“…Exogenous toxins are often activated after mixed function oxidase-catalyzed reactions in the endoplasmic reticulum; glucuronidation usually redutes the biological activity of these metabolites (37); however, in certain instances glucuronidation may result in the formation of a proximate or ultimate carcinogen (38,39). From both points of view, the localization of the transferases in the endoplasmic reticulum and nuclear envelope may be of functional significance.…”

Section: Discussionmentioning

confidence: 99%

Distribution of UDPglucuronosyltransferase in rat tissue.

Chowdhury¹,

Novikoff²,

Chowdhury³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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UDPglucuronosyltransferase [UDPglucuronate 13-D-glucuronosyltransferase (acceptor-unspecific), EC 2.4.1.17] is a group of enzymes with distinct but partially overlapping substrate specificity. A rabbit antiserum raised against one purified rat liver UDPglycuronosyltransferase isoform was specific for UDPglucuronosyltransferase and recognized all transferase isoforms by immunodiffusion or immunotransblot analysis. The transferase activity toward all substrates was immunoabsorbed from solubilized rat liver microsomes by IgG purified from the antiserum. The purified IgG was used for immunocytochemical localization of UDPglucuronosyltransferase in rat liver, jejunum, kidney, and adrenal gland. In the liver, UDPglucuronosyltransferase was present exclusively in hepatocytes and was uniformly distributed within all zones of the hepatic lobule. In the jejunum, the transferase was present exclusively in the epithelial cells and showed a progressive increase in concentration from the crypt to the villar tip. In the kidney, the greatest concentration of the transferase was observed in the epithelial cells of the proximal convoluted tubule. Adrenal medullary cells showed intense immunocytochemical staining; the zona glomerulosa and the zona reticularis of the adrenal cortex were more intensely stained than the zona fasciculata. By light microscopy, UDPglucuronosyltransferase was found in the endoplasmic reticulum and nuclear envelope of all the four organs; this was confirmed in the hepatocyte by electron microscopy. The transferase was not observed in mitochondria, Golgi apparatus, lysosomes, peroxisomes, and plasma membrane, even after 3-to 4-fold induction of various substrate-specific UDPglucuronosyltransferase activities.

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Section: Discussionmentioning

confidence: 99%

Distribution of UDPglucuronosyltransferase in rat tissue.

Chowdhury¹,

Novikoff²,

Chowdhury³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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“…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%

“…An important pathway in the conversion of aromatic amines to ultimate carcinogenic metabolites is N-acetylation followed by N-hydroxylation to form the hydroxamic acid derivatives; these, subsequently, are substrates for conjugation (1,2). The main products are the relatively stable glucuronides and the more labile sulfate conjugates of the N-hydroxy group (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

“…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%

See 1 more Smart Citation

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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“…A case in which conjugation leads to the formation of the ultimate carcinogenic intermediate is the conjugation of sulfate with N-hydroxy-acetylaminofluorene in liver of rats (85,110). Irving and co-workers (86) could not detect the enzymic O-sulfonation of Nhydroxy-acetylaminofluorene in the sebaceous glands associated with the external auditory meatus of rats, a target tissue ofthe fluorene derivative, and they suggested that the ultimate carcinogenic form of the acetylaminofluorene might differ in liver and in the skin appendages (86).…”

Section: Conjugasesmentioning

confidence: 98%