Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion

Kadlubar, Fred F.; Unruh, Leonard E.; Flammang, Thomas J.; Sparks, Daniel L.; Mitchum, R. K.; Mulder, Gerard J.

doi:10.1016/0009-2797(81)90036-3

Cited by 75 publications

(24 citation statements)

References 38 publications

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“…N-glucuronides accumulation in workers, as indicated by the high levels of MIβ mutagenicity in relation to controls, may represent a risk factor of higher exposure to mutagens in their bladders. Arylamine N-glucuronides are labile and may be easily hydrolysed to hydroxylamines in the weak acidic media of the urinary bladder 33) . These hydroxylamines can lose water to yield an electrophilic arylnitrenium ion which can, in turn, react with DNA and macromolecules and initiate tumorigenesis 34) .…”

Section: Discussionmentioning

confidence: 99%

Urinary Mutagenicity, CYP1A2 and NAT2 Activity in Textile Industry Workers

Fanlo¹,

Sinués²,

Mayayo³

et al. 2004

Journal of Occupational Health

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Urinary Mutagenicity, CYP1A2 and NAT2 Activity in Textile Industry Workers: Ana FANLO, et al. Department of Pharmacology and Physiology, University of Zaragoza, Spain-The two major causes of bladder cancer have been recognised to be cigarette smoke and occupational exposure to arylamines. These compounds are present both in tobacco smoke and in the dyes used in textile production. Aromatic amines suffer oxidative metabolism via P450 cytochrome CYP1A2, and detoxification by the polymorphic NAT2. The aim of the present work was to assess the association between occupational-derived exposure to mutagens and CYP1A2 or NAT2 activity. This cross-sectional study included 117 textile workers exposed to dyes and 117 healthy controls. The urinary mutagenicity was determined in 24 h urine using TA98 Salmonella typhimurium strain with microsomal activation S9 (MIS9) or incubation with β-glucuronidase (MIβ). Urinary caffeine metabolite ratios: AFMU+1X+1U/17U, and AFMU/AFMU+1X+1U were calculated to assess CYP1A2 and NAT2 activities, respectively. The results show that workers present a strikingly higher urine mutagenicity than controls (p<0.0001), despite the implementation of the new restrictive norms forbidding the industrial use of the most carcinogenic arylamines. Neither NAT2 nor CYP1A2 activity had any effect on the markers of internal exposure to mutagens, since no significant differences were observed when the urinary mutagenicity of slow and fast acetylators (p>0.05) was compared, and the urinary mutagenicity was not significantly associated with the CYP1A2 activity marker (r=0.04 and r=-0.01 for MIS9 and MIβ, respectively). This study clearly indicates the need for further protective policies to minimise exposure to the Received May 10, 2004; Accepted Sep 6, 2004 Correspondence to: B. Sinués, Department of Pharmacology, Medicine School, University of Zaragoza, Domingo Miral s/n, 50009 Zaragoza, Spain (e-mail: bsinues@posta.unizar.es) lowest feasible limit in order to avoid unnecessary risks.

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Section: Discussionmentioning

confidence: 99%

Urinary Mutagenicity, CYP1A2 and NAT2 Activity in Textile Industry Workers

Fanlo¹,

Sinués²,

Mayayo³

et al. 2004

Journal of Occupational Health

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“…These polar metabolites are quite stable at neutral pH; however, under slightly acidic conditions, they rapidly hydrolyze to the unconjugated N-hydroxyarylamines (8). The importance of urinary pH in the formation of these Nhydroxy metabolites has recently been demonstrated in rats treated with 2-naphthylamine (15). Rats normally have a urinary pH of 6.7 but by supplementation of their drinking water with either ammonium chloride or sodium bicarbonate, the pH of the urine was altered to 5.7 and 7.7, respectively.…”

Section: Introductionmentioning

confidence: 99%

Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis

Beland¹,

Beranek²,

Dooley³

et al. 1983

Environ Health Perspect

176

126

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Hepatic N-oxidation, followed by N-glucuronidation, has been proposed as a route of metabolic activation for arylamine bladder carcinogens. It is postulated that the N-glucuronides are transported to the bladder lumen where they are hydrolyzed under slightly acidic conditions to release directacting carcinogenic and mutagenic N-hydroxyarylamines. In this study, 4-aminobiphenyl (ABP), 1-naphthylamine (1-NA), 2-naphthylamine (2-NA), 2-acetylaminofluorene (AAF), 4-nitrobiphenyl (NBP), benzidine (BZ), and N-acetylbenzidine (ABZ) were administered to male beagle dogs (60 mmole/kg), and the bladder epithelium DNA adducts were quantified at various times after treatment. At 24-48 hr after administration, the order of binding to bladder epithelium DNA was: ABP >> AAF > NBP 2-NA-BZ ABZ>> 1-NA. The level of DNA modification by ABP remained constant for 7 days, whereas 2-NA and AAF residues decreased by 35% and 80%, respectively. The extent and relative persistence of total DNA binding correlated with the compounds' ability to induce bladder tumors in dogs. ABP, AAF, NBP, 2-NA and ABZ administration resulted in DNA binding sufficient for adduct analysis. Enzymatic hydrolysis of the DNA and examination of the adducts by high pressure liquid chromatography indicated that arylamine substitution at C8 of deoxyguanosine was the dominant product. Additional adducts were detected in animals treated with ABP, NBP, and 2-NA. Furthermore, the profiles of adducts obtained in vivo were remarkably similar to the profiles obtained when the N-hydroxy arylamine metabolites of these carcinogens were reacted with DNA in vitro at pH 5.0. To evaluate the mutagenic potential of these arylamine-DNA adducts, Salmonella typhimurium strains TA 1535 and TA 1538 were incubated with N-hydroxy-2-NA, N-hydroxy-2-aminofluorene (AF), N-hydroxy-ABP, and N-hydroxy-ABZ and the resulting DNA adducts and reversions were quantified. Arylamine-C8-deoxyguanosine substitution was correlated with frameshift reversions induced by these agents, with the lesions showing a relative order of mutagenic efficiency of ABZ>AF-2-NA>ABP. These data suggest that mutagenic N-hydroxyarylamines may be ultimate carcinogens for the bladder epithelium. Furthermore, if one assumes that a mutagenic lesion is important for tumor initiation, then C8-deoxyguanosine substitution by these compounds may be significant for urinary bladder carcinogenesis.

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“…Thus, the role of the N-glucuronide of N-hydroxy-2-naphthylamine in bladder carcinogenesis (13) can be evaluated directly. However, if a glucuronide is only effective inside the cell, such studies may not be possible since most likely the glucuronides will be taken up only slightly by cells due to the poor lipid solubility of these compounds.…”

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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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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Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion

Cited by 75 publications

References 38 publications

Urinary Mutagenicity, CYP1A2 and NAT2 Activity in Textile Industry Workers

Urinary Mutagenicity, CYP1A2 and NAT2 Activity in Textile Industry Workers

Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis

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

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