Lactoperoxidase-catalyzed activation of carcinogenic aromatic and heterocyclic amines.
Lactoperoxidase, an enzyme secreted from the human mammary gland, plays a host defensive role through antimicrobial activity. It has been implicated in mutagenic and carcinogenic activation in the human mammary gland. The potential role of heterocyclic and aromatic amines in the etiology of breast cancer led us to examination of the lactoperoxidase-catalyzed activation of the most commonly studied arylamine carcinogens: 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), benzidine, 4-aminobiphenyl (ABP), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). In vitro activation was performed with lactoperoxidase (partially purified from bovine milk or human milk) in the presence of hydrogen peroxide and calf thymus DNA. Products formed during enzymatic activation were monitored by HPLC with ultraviolet and radiometric detection. Two of these products were characterized as hydrazo and azo derivatives by means of mass spectrometry. The DNA binding level of 3H- and 14C-radiolabeled amines after peroxidase-catalyzed activation was dependent on the hydrogen peroxide concentration, and the highest levels of carcinogen binding to DNA were observed at 100 microM H2O2. Carcinogen activation and the level of binding to DNA were in the order of benzidine > ABP > IQ > MeIQx > PhIP. One of the ABP adducts was identified, and the level at which it is formed was estimated to be six adducts/10(5) nucleotides. The susceptibility of aromatic and heterocyclic amines for lactoperoxidase-catalyzed activation and the binding levels of activated products to DNA suggest a potential role of lactoperoxidase-catalyzed activation of carcinogens in the etiology of breast cancer.
Gorlewska-Roberts
Katarzyna M
KM
National Center for Toxicological Research, HFT 100, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.
Teitel
Candee H
CH
Lay
Jackson O
JO
Roberts
Dean W
DW
Kadlubar
Fred F
FF
D000588:Amines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002417:Cattle; D018736:DNA Adducts / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006571:Heterocyclic Compounds / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000378:metabolism / Q000633:toxicity; D007784:Lactoperoxidase / Q000378:metabolism*; D008895:Milk, Human / Q000737:chemistry / Q000201:enzymology; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization
D000588:Amines; D002273:Carcinogens; D018736:DNA Adducts; D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D007784:Lactoperoxidase