Influence of beta-naphthoflavone on 7,12-dimethylbenz(a)anthracene metabolism, DNA adduction, and tumorigenicity in rainbow trout.
Metabolism, DNA adduction, and tumor induction by 7, 12-dimethylbenz(a)anthracene (DMBA) were examined in cultured trout liver cells and in vivo in trout. Modulating CYP1A1 activity indicated this enzyme plays a significant role in metabolizing DMBA to water-soluble compounds in isolated trout liver cells. The major DMBA metabolites identified in trout liver cells were 10-, 11-, 8,9-, and 5,6-DMBA dihydrodiols, and DMBA, 2- or 3- or 4-phenol; 7-OH-methyl-12-methyl-benz(a)anthracene and 12-OH-methyl-7-methyl-benz(a)anthracene were minor metabolites. A very small amount of DMBA-3,4-dihydrodiol was detected, and polar metabolites, which did not migrate with any DMBA metabolite standards, were observed. Incubating trout hepatocytes with DMBA-3, 4-dihydrodiol produced three prominent, nonpolar adducts indistinguishable from those in mouse embryo cells. However, DMBA-DNA adducts, formed in trout in vivo or in trout liver cells exposed to DMBA, were predominantly more polar than those formed in mouse embryo fibroblasts, and levels of DMBA-DNA adducts formed in trout liver cells were not significantly altered by modulating CYP1A1 activity. No significant repair of DMBA-DNA adducts was detected in cultured trout liver cells over a 48-h period, supporting previous studies indicating that fish are less efficient than mammals in repairing polyaromatic hydrocarbon DNA adducts. Compared to animals receiving DMBA alone, beta-naphthoflavone pretreatment in vivo did not affect hepatic CYP1A1, DMBA-DNA adducts, nor hepatic tumor response; but did significantly reduce tumor response in two other target organs. These results collectively indicate that DMBA bioactivation to DNA-binding metabolites in trout liver cells and mouse embryo cells predominantly involve different metabolic pathways to form the DNA-binding intermediates.
Weimer
T L
TL
Department of Pharmacology and Toxicology, West Virginia University, Morgantown, West Virginia 26506, USA.
Reddy
A P
AP
Harttig
U
U
Alexander
D
D
Stamm
S C
SC
Miller
M R
MR
Baird
W
W
Hendricks
J
J
Bailey
G
G
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001571:Benzoflavones / Q000008:administration & dosage / Q000633:toxicity; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair; D004032:Diet; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D017686:Oncorhynchus mykiss; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000633:toxicity*
D001571:Benzoflavones; D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D015127:9,10-Dimethyl-1,2-benzanthracene; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1