32P-postlabeling analysis of the DNA adducts of 6-fluorobenzo[a]pyrene and 6-methylbenzo[a]pyrene formed in vitro.
Studies of benzo[a]pyrene (BP) and selected derivatives are part of the strategy to elucidate mechanisms of tumor initiation by polycyclic aromatic hydrocarbons. Substitution of BP at C-6 with fluorine to form 6-fluorobenzo[a]pyrene (6-FBP) or a methyl group to form 6-methylbenzo[a]pyrene (6-CH3BP) decreases tumorigenicity compared to BP. BP, 6-FBP, and 6-CH3BP formed adducts with DNA when (1) they were activated by 3-methylcholanthrene-induced rat liver microsomes, (2) they were activated by horseradish peroxidase (HRP), (3) their 7,8-dihydrodiols were activated by microsomes, or (4) the radical cation of BP, 6-FBP, or 6-CH3-BP was directly reacted with DNA. With microsomes, 6.5 mumol of [3H]6-FBP/mol of DNA-P and 10 mumol of [14C]6-CH3BP/mol of DNA-P were bound vs 15 mumol of [3H]BP. With microsomes, two major 6-FBP adducts and some minor adducts were obtained. One major adduct coincided with that from 6-FBP-7,8-dihydrodiol. With microsomes, the minor 6-FBP adducts coincided with the adducts obtained from 6-FBP radical cation plus DNA and the major adduct of HRP-activated 6-FBP. With microsomes, 6-CH3BP showed adducts similar to some formed with HRP and one from 6-CH3BP radical cation. 6-CH3BP-7,8-dihydrodiol produced a small amount of one adduct that did not coincide with any from 6-CH3BP. The adducts of 6-FBP appear to be formed mostly through the diolepoxide pathway, whereas those of 6-CH3BP appear to arise mostly via one-electron oxidation.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805.
R
R
Todorovic
P D
PD
Devanesan
E G
EG
Rogan
E L
EL
Cavalieri
D000818:Animals; D001345:Autoradiography; D001580:Benzopyrenes / Q000032:analysis*; D002273:Carcinogens / Q000032:analysis*; D002855:Chromatography, Thin Layer; D004247:DNA / Q000032:analysis*; D006735:Horseradish Peroxidase; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008748:Methylcholanthrene / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010761:Phosphorus Radioisotopes; D011083:Polycyclic Compounds / Q000378:metabolism; D051381:Rats
D001580:Benzopyrenes; D002273:Carcinogens; D010761:Phosphorus Radioisotopes; D011083:Polycyclic Compounds; C017503:6-methylbenzo(a)pyrene; D008748:Methylcholanthrene; C012323:6-fluorobenzo(a)pyrene; D004247:DNA; D006735:Horseradish Peroxidase