Bioactivation of the proximal food mutagen 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) to DNA-binding species by human mammary gland enzymes.
We have investigated phase II activation of the food-derived mutagen 2-hydroxyamino-1-methyl-6-phenyl[4,5-b]pyridine (N-OH-PhIP) by cytosolic acetyltransferase, sulfotransferase, and tRNA synthetase/kinase enzymes from human breast tissue. Cytosol from homogenates of mammary gland tissue obtained from breast-reduction surgery or mastectomy was incubated with and without enzyme-specific cofactors, and mutagen binding of calf thymus DNA was quantified by 32P-postlabeling. In addition, microsomal fractions of mammary epithelial cells from some individuals were examined for prostaglandin H synthetase activation of N-OH-PhIP. Our results show that all four enzymes can participate in activating N-OH-PhIP, thus inducing PhIP-DNA adduct formation in human mammary cells. However, not all individuals exhibited all these activities; instead each individual showed a combination of one or more activation pathways. The present findings demonstrate that the human mammary gland has the capacity to metabolically activate a dietary mutagen by several enzyme systems, including acetyltransferase, sulfotransferase, tRNA synthetase/kinase, and prostaglandin hydroperoxidase catalysis.
Dubuisson
J G
JG
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, USA.
Gaubatz
J W
JW
D000123:Acetyltransferases / Q000378:metabolism; D000328:Adult; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D004951:Esterification; D005260:Female; D005502:Food; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000201:enzymology*; D008875:Middle Aged; D009153:Mutagens; D011725:Pyridines / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism
D018736:DNA Adducts; D007093:Imidazoles; D009153:Mutagens; D011725:Pyridines; C060533:2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000123:Acetyltransferases; D015238:Sulfotransferases; D000604:Amino Acyl-tRNA Synthetases