title: Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism.
abstract: Recent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer. Rat NAT2 is orthologous to human NAT1 and the gene products are functional homologs. We conducted in vivo studies using F344.WKY-Nat2rapid/slowrats, congenic at rat Nat2 for high (rapid) and low (slow) arylamine N-acetyltransferase activity, to assess a possible role for rat NAT2 in mammary tumor susceptibility.
  
  
  
  Mammary carcinogens, methylnitrosourea (MNU) and 7,12-dimethylbenzanthracene (DMBA) neither of which is metabolized by N-acetyltransferase, were administered to assess mammary tumors. MNU was administered at 3 or 8 weeks of age. DMBA was administered at 8 weeks of age. NAT2 enzymatic activity and endogenous acetyl-coenzyme A (AcCoA) levels were measured in tissue samples and embryonic fibroblasts isolated from the congenic rats.
  
  
  
  Tumor latency was shorter in rapid NAT2 rats compared to slow NAT2 rats, with statistical significance for MNU administered at 3 and 8 weeks of age (p = 0.009 and 0.050, respectively). Tumor multiplicity and incidence were higher in rapid NAT2 rats compared to slow NAT2 rats administered MNU or DMBA at 8 weeks of age (MNU, p = 0.050 and 0.035; DMBA, p = 0.004 and 0.027, respectively). Recombinant rat rapid-NAT2, as well as tissue samples and embryonic fibroblasts derived from rapid NAT2 rats, catalyzed p-aminobenzoic acid N-acetyl transfer and folate-dependent acetyl-coenzyme A (AcCoA) hydrolysis at higher rates than those derived from rat slow-NAT2. Embryonic fibroblasts isolated from rapid NAT2 rats displayed lower levels of cellular AcCoA than slow NAT2 rats (p < 0.01).
  
  
  
  A novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.|James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Stepp
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.|James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.|Department of Biochemistry & Molecular Genetics, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Samuelson
authors.affiliation: Department of Pathology, University of Louisville Hospital, Louisville, KY, 40202, USA.
authors.forename: Mary Ann G
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.|James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA. d.hein@louisville.edu.|James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA. d.hein@louisville.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D004198:Disease Susceptibility; D005260:Female; D008658:Inactivation, Metabolic; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY
chemical_list: D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D001191:Arylamine N-Acetyltransferase; C541077:NAT2 protein, rat
keywords: 7,12-dimethylbenzanthracene (DMBA); Acetyl-coenzyme A (AcCoA); Chemically-induced tumorigenesis; Human arylamine N-acetyltransferase 1 (NAT1); Methylnitrosourea (MNU); Rat arylamine N-acetyltransferase 2 (NAT2)