In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice

Sugamori, Kim S.; Brenneman, Debbie; Grant, Denis M.

doi:10.1124/dmd.106.010819

Cited by 30 publications

(21 citation statements)

References 40 publications

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“…In addition, no difference in the in vivo plasma elimination of PAS, ABP, AF, or SMZ was observed between Nat3(Ϫ/Ϫ) and wild-type mice. This concurs with the in vivo results seen with our Nat1/2(Ϫ/Ϫ) mice, in which we were unable to detect any acetylated metabolites in the knockout animals at the level of sensitivity of our assays (Sugamori et al, 2003(Sugamori et al, , 2006. The presence of acetylated metabolites in mice lacking both Nat1 and Nat2 would have indicated possible N-acetylation by Nat3.…”

Section: Arylamine N-acetyltransferase Nat3(ϫ/ϫ) Knockout Micesupporting

confidence: 78%

“…Our results indicate that there is no decrease in cytosolic NAT activity for a number of substrates in our Nat3(Ϫ/Ϫ) animals. The gender difference in kidney PAS, ABP, and AF acetylation (Sugamori et al, 2003(Sugamori et al, , 2006 was seen in both the wild-type and Nat3(Ϫ/Ϫ) mice. In addition, no difference in the in vivo plasma elimination of PAS, ABP, AF, or SMZ was observed between Nat3(Ϫ/Ϫ) and wild-type mice.…”

Section: Arylamine N-acetyltransferase Nat3(ϫ/ϫ) Knockout Micementioning

confidence: 98%

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Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse

Sugamori¹,

Brenneman²,

Wong³

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:Arylamine N-acetyltransferases (NAT) catalyze the biotransformation of many important arylamine drugs and procarcinogens. NAT can either detoxify or activate procarcinogens, complicating the manner in which these enzymes may participate in enhancing or preventing toxic responses to particular agents. Mice possess three NAT isoenzymes: Nat1, Nat2, and Nat3. Whereas Nat1 and Nat2 can efficiently acetylate many arylamines, few substrates appear to be appreciably metabolized by Nat3. We generated a Nat3 knockout mouse strain and used it along with our double Nat1/2(؊/؊) knockout strain to further investigate the functional role of Nat3. Nat3(؊/؊) mice showed normal viability and reproductive capacity. Nat3 expression was very low in wild-type animals and completely undetectable in Nat3(؊/؊) mice. In contrast, greatly elevated expression of Nat3 transcript was observed in Nat1/2(؊/؊) mice. We used a transcribed marker polymorphism approach to establish that the increased expression of Nat3 in Nat1/2(؊/؊) mice is a positional artifact of insertion of the phosphoglycerate kinase-neomycin resistance cassette in place of the Nat1/Nat2 gene region and upstream of the intact Nat3 gene, rather than a biological compensatory mechanism. Despite the increase in Nat3 transcript, the N-acetylation of p-aminosalicylate, sulfamethazine, 2-aminofluorene, and 4-aminobiphenyl was undetectable either in vivo or in vitro in Nat1/2(؊/؊) animals. In parallel, no difference was observed in the in vivo clearance or in vitro metabolism of any of these substrates between wild-type and Nat3(؊/؊) mice. Thus, Nat3 is unlikely to play a significant role in the N-acetylation of arylamines either in wild-type mice or in mice lacking Nat1 and Nat2 activities.

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Section: Arylamine N-acetyltransferase Nat3(ϫ/ϫ) Knockout Micesupporting

confidence: 78%

Section: Arylamine N-acetyltransferase Nat3(ϫ/ϫ) Knockout Micementioning

confidence: 98%

Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse

Sugamori¹,

Brenneman²,

Wong³

et al. 2007

Drug Metabolism and Disposition

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“…However, the relevance of this pathway to AA tolerance in living organisms has remained unclear. So far, studies done on knock-out NAT mouse models have not demonstrated a role for NAT enzymes in preventing AA toxicity (21). Our P. anserina model provides the first clear molecular and functional evidence indicating that the NATdependent xenobiotic-biotransformation pathway can afford complete tolerance toward toxic AA in a eukaryotic organism.…”

Section: Detoxification Of the Highly Toxic Pesticide Residue 34-dcamentioning

confidence: 92%

“…In eukaryotes, NAT enzymes have long been known to biotransform AA (20). However, it is still unclear what role NAT enzymes actually play in either preventing or enhancing toxic response to AA (21). So far, the studies on the knock-out NAT mouse models (21-23) have not demonstrated clearly the relevance of this pathway to AA tolerance in living organisms.…”

Section: Identification and Characterization Of P Anserina Nat Enzymmentioning

confidence: 99%

An Acetyltransferase Conferring Tolerance to Toxic Aromatic Amine Chemicals

Martins

Rodrigues‐Lima

Dairou

et al. 2009

Journal of Biological Chemistry

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Aromatic amines (AA) are a major class of environmental pollutants that have been shown to have genotoxic and cytotoxic potentials toward most living organisms. Fungi are able to tolerate a diverse range of chemical compounds including certain AA and have long been used as models to understand general biological processes. Deciphering the mechanisms underlying this tolerance may improve our understanding of the adaptation of organisms to stressful environments and pave the way for novel pharmaceutical and/or biotechnological applications. We have identified and characterized two arylamine N-acetyltransferase (NAT) enzymes (PaNAT1 and PaNAT2) from the model fungus Podospora anserina that acetylate a wide range of AA. Targeted gene disruption experiments revealed that PaNAT2 was required for the growth and survival of the fungus in the presence of toxic AA. Functional studies using the knock-out strains and chemically acetylated AA indicated that tolerance of P. anserina to toxic AA was due to the N-acetylation of these chemicals by PaNAT2. Moreover, we provide proof-of-concept remediation experiments where P. anserina, through its PaNAT2 enzyme, is able to detoxify the highly toxic pesticide residue 3,4-dichloroaniline in experimentally contaminated soil samples. Overall, our data show that a single xenobiotic-metabolizing enzyme can mediate tolerance to a major class of pollutants in a eukaryotic species. These findings expand the understanding of the role of xenobiotic-metabolizing enzyme and in particular of NATs in the adaptation of organisms to their chemical environment and provide a basis for new systems for the bioremediation of contaminated soils.

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“…ABP was purified by the manufacturer by thin-layer chromatography to >99% purity, and it eluted as a single chromatographic peak by reverse-phase high performance liquid chromatography (HPLC) using UV detection at 280 nm and previously described chromatographic conditions [Sugamori et al, 2006]. All procedures involving animals were performed in accordance with Canadian Council on Animal Care guidelines.…”

Section: Chemicals and Animal Treatmentmentioning

confidence: 99%

Influence of arylamine n‐acetyltransferase, sex, and age on 4‐aminobiphenyl‐induced in vivo mutant frequencies and spectra in mouse liver

Wang

Sugamori

Brenneman

et al. 2012

Environ and Mol Mutagen

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One model for cancer initiation by 4-aminobiphenyl (ABP) involves N-oxidation by cytochrome P450 CYP1A2 followed by O-conjugation by Nacetyltransferase(s) NAT1 and/or NAT2 and decomposition to a DNA-binding nitrenium ion. We recently observed that neonatal ABP exposure produced liver tumors in male but not in female mice, and that NAT deficiency reduced liver tumor incidence. However, ABP-induced liver tumor incidence did not correlate with liver levels of N-(deoxyguanosin-8-yl)-ABP adducts 24 hr after exposure. In this study, we compared in vivo ABPinduced DNA mutant frequencies and spectra between male and female wild-type and NATdeficient Muta TM Mouse using both the tumorinducing neonatal exposure protocol and a 28-day repetitive dosing adult exposure protocol. ABP produced an increase in liver DNA mutant frequencies in both neonates and adults. However, we observed no sex or strain differences in mutant frequencies in neonatally exposed mice, and higher frequencies in adult females than males. Neonatal ABP exposure of wild-type mice increased the proportion of G-T transversions in both males and females, while exposure of Nat1/2(-/-) mice produced increased G-T transversions in males and a decrease in females, even though females had higher levels of N-(deoxyguanosin-8-yl)-4-ABP adducts. There was no correlation of mutant frequencies or spectra between mice dosed as neonates or as adults. These results suggest that observed sex-and NATdependent differences in ABP-induced liver tumor incidence in mice are not due to differences in either mutation rates or mutational spectra, and that mechanisms independent of carcinogen bioactivation, covalent DNA binding and mutation may be responsible for these differences. Environ. Mol. Mutagen. 53:350-357, 2012. V V C 2012 Wiley Periodicals, Inc.

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In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice

Cited by 30 publications

References 40 publications

Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse

Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse

An Acetyltransferase Conferring Tolerance to Toxic Aromatic Amine Chemicals

Influence of arylamine n‐acetyltransferase, sex, and age on 4‐aminobiphenyl‐induced in vivo mutant frequencies and spectra in mouse liver

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