Glucuronidation of <i>N</i>-hydroxy metabolites of <i>N</i>-acetylbenzidine

Babu, S. Ramesh; Lakshmi, Vijaya M.; Hsu, Fong‐Fu; Zenser, Terry V.; Davis, Bernard B.

doi:10.1093/carcin/16.12.3069

Cited by 29 publications

(25 citation statements)

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“…In aqueous solutions, chemically synthesized N-acetyl-IQ was stable, whereas N-acetyl-demethyl-IQ was not stable. In addition, the N-glucuronides of aromatic amines are quite acid-labile, i.e., the N-glucuronide of N-acetylbenzidine has a half-life at pH 5.5 of approximately 8 min (Babu et al, 1995), whereas N-glucuronides of these heterocyclic amines are relatively acid-stable (see Materials and Methods). Results suggest that the chemistry involving the exocyclic amine of these heterocyclic compounds is different from that of aromatic amines and may also contribute to the lack or low rate of N-acetylation of heterocyclic amines.…”

Section: Iq Metabolites Produced By Mouse Liver Slicesmentioning

confidence: 99%

N-Demethylation Is a Major Route of 2-Amino-3-Methylimidazo[4,5-f]quinoline Metabolism in Mouse

Lakshmi¹,

Hsu²,

Zenser³

2008

Drug Metab Dispos

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2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is a heterocyclic amine (HCA) formed by high-temperature cooking of proteinaceous food (Felton and Knize, 1990). More than 20 similarly formed HCAs have been identified. In the human diet, consumption of 400 g of cooked lean meat could result in exposure to several micrograms of mutagenic HCAs. These amines are detected in urine and their excretion, as unchanged amine, is increased by a cytochrome P450 (P450) inhibitor (Lynch et al., 1992;Boobis et al., 1994), indicating their absorption from cooked foods and P450 metabolism.IQ is a potent carcinogen inducing tumors in multiple tissues and in different species (National Toxicology Program Report on Carcinogens: Background Document for Heterocyclic Amines: MeIQ, MeIQx, IQ, and PhIP, 2005, http://ntp.niehs.nih.gov/ntp/roc/eleventh/ profiles/s092vhca.pdf). In mouse, oral administration of IQ caused forestomach, liver, and lung tumors in both sexes. Although IQ also caused tumors in several organs in both sexes of rats, mammary and clitoral gland tumors were only detected in females and colon and skin tumors only in males. IQ administered orally to monkeys or mice caused liver tumors. Using a colitis-induced carcinogenicity model with ApcMin/ϩ mice (Cooper et al., 2001), we have preliminary data indicating that induction of colitis by treatment with 4% dextran sulfate sodium (DSS) in drinking water followed by oral doses of 40 mg/kg IQ resulted in a 100% incidence of invasive colorectal tumors, whereas mice treated with only DSS had no tumors (Clapper et al., 2006). The strong association of intake of high-temperature cooked meat and colorectal cancer risk (Giovannucci et al., 1994), the presence of HCAs in cooked meat (Felton and Knize, 1990), and the initiation of colon cancer by HCAs (Kristiansen et al., 1997) suggest that HCAs present in high-temperature cooked meat may be responsible for the increased risk of colon cancer associated with this dietary component.Activation of IQ is thought to involve N-oxidation by P450, followed by O-acetylation with subsequent formation of a reactive intermediate, nitrenium ion, that binds DNA (Turesky et al., 1991). These DNA adducts are thought to cause mutations that initiate carcinogenesis. After IQ administration, DNA adducts are found in a variety of rodent and nonhuman primate tissues (Nerurkar et al., 1995;Turesky et al., 1996). Whereas N-oxidation of IQ has been demonstrated with rat microsomes (Turesky et al., 1998), excretion of

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Section: Iq Metabolites Produced By Mouse Liver Slicesmentioning

confidence: 99%

N-Demethylation Is a Major Route of 2-Amino-3-Methylimidazo[4,5-f]quinoline Metabolism in Mouse

Lakshmi¹,

Hsu²,

Zenser³

2008

Drug Metab Dispos

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“…9 Zenser's group has reported that N 0 -OH-N 0 -glucuronide-N-acetylbenzidine can not be hydrolyzed using a metabolite prepared from N 0 -OH-N-acetylbenzidine in the presence of a glucuronosyltransferase system. 10 From a chemical structure viewpoint, the stability of this conjugate is not expected to be different from the N-OH-N-glucuronide of 2-aminofluorene, 4-aminobiphenyl and 2-aminonapthalene. The N-OH-N-glucuronide of these monoamines can be hydrolyzed in neutral or acidic pH, albeit the rate is slower at higher pHs.…”

Section: Dear Sirmentioning

confidence: 96%

Metabolic activation of benzidine

Wang

King²

2007

Intl Journal of Cancer

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Dear Sir,In reviewing the response by Carreon et al., 1 the framework of our conclusions regarding studies concerning benzidine can be summarized as follows.The mechanisms by which benzidine causes urinary bladder cancer is of scientific interest and, more importantly, as a public health issue. As stated in our original communication, 2 we agree with Carreon et al. that rapid acetylators appear to be at greater risk. 3 Our primary concern with their original paper and their response is that they give unwarranted strength to the idea that prostanglandin H synthase (PHS) is involved in the activation of N-acetylbenzidine to N 0 -hydroxy-N-acetylbenzidine in the urothelium, a target of benzidine in humans.We agree with their newly submitted proposed metabolic scheme that PHS is unlikely to produce a reactive metabolite in the urothelium. This is consistent with previous studies comparing the activation of benzidine and N-acetylbenzidine by PHS. The experimental evidence provided in Table I is from Morton et al. 4 As can be seen, PHS activation of N-acetylbenzidine is less than 1% that of benzidine, about one half that of 2-aminofluorene or 2-aminonaphthalene and slightly greater than 4-aminobiphenyl.Recognition of Zenser's ability to detect N 0 -hydroxy-N-acetylbenzidine on incubation with N-acetylbenzidine and PHS is not convincing that it would actually influence DNA modification in the urothelium. 5 If this were to be the case, one could argue that activation by PHS would be important for simple aromatic monoamines such as 2-aminofluorene and 2-aminonaphthalene.It is likely that most investigators in this area would agree that the presentation of N-oxidized aromatic amines to the urothelium is probably a crucial requirement for a carcinogenic outcome. A final metabolic transformation, such as the production of a reactive species by O-acetylation, would provide for chemical modification of DNA within the urothelial cell.The oxidized derivatives are generally believed to be derived from the urine; urinary diversion in the dog abolished the bladder carcinogenicity of 2-aminonaphthalene. 6 Much attention has been given to the possibility that urinary pH is involved in the stabilization, or activation, of various N-oxidized metabolites. The idea that the lower pH of urine might stabilize some N-oxidized metabolites would seem to be more important than the enhancement of modification of DNA by these metabolites. This comes from recognition that decreases in tightly regulated intracellular pH would be expected to compromise cellular viability and not provide for survival of modified cells capable of the development of tumors. Previous studies that have isolated benzidine-DNA adducts from exfoliated cells in the urine cannot exclude the possibility that these adducts came from acid-catalyzed reactions of hydroxylamines with nonviable cells that no longer had intact external cellular membranes. 7 We agree that the question of the identification of metabolites that are unstable, as with many of the postulated benzidine de...

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“…These observations are consistent with the hypothesis that N-acetylbenzidine-glucuronide may have an important role in benzidine carcinogenesis, as Zenser et al have shown that this compound is extremely acid labile with its half-life reduced to several minutes under acidic conditions in urine. 8,9 In contrast, it is unlikely that DNA adduct formation would have been influenced by urine acidity if N 0 À ÀOHÀ ÀN-acetylbenzidine-N 0 -glucuronide was the only adduct forming agent, because this glucuronide is much more stable under acidic pH conditions, with a long half-life. 8,9 As such, the observations of Drs.…”

Section: Dear Sirmentioning

confidence: 99%

“…8,9 In contrast, it is unlikely that DNA adduct formation would have been influenced by urine acidity if N 0 À ÀOHÀ ÀN-acetylbenzidine-N 0 -glucuronide was the only adduct forming agent, because this glucuronide is much more stable under acidic pH conditions, with a long half-life. 8,9 As such, the observations of Drs. Wang and King, based on the heterotopic bladder model, may not be generalizable, as this model does not mimic urine flow and urine pH, key components of aromatic amine carcinogenesis in human [a substantial proportion of humans have urine pH at or below pH 6.0 (N. Rothman, unpublished data)].…”

Section: Dear Sirmentioning

confidence: 99%