Detection of the major DNA adducts of benzo[b]fluoranthene in mouse skin: Role of phenolic dihydrodiols

Journal Article · · Chemical Research in Toxicology; (United States)

DOI:https://doi.org/10.1021/tx00034a028· OSTI ID:7060390

Weyand, E H; Cai, Z W; Wu, Y; Rice, J E; He, Z H; LaVoie, E J ^[1]

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1. State Univ. of New Jersey, Piscataway, NJ (United States)

The primary mechanism of activation of benzo[b]fluoranthene (B[b]F) to a genotoxic agent does not involve the bay region dihydrodiol epoxide trans-9,10-dihydroxy-anti-11,12-epoxy-9,10,11,12-tetrahydrobenzo[b]fluoranthene (B[b]F-9,10-DE). Previous results have suggested that the major DNA adduct(s) formed in vivo with B[b]F are more polar than those formed from B[b]F-9,10-DE. Employing newly-developed synthetic methods, trans-9,10-dihydro-5,9,10-trihydroxybenzo[b]fluoranthene (5-OH-B[b]F-9,10-diol) and trans-9,10-dihydro-6,9,10-trihydroxybenzo[b]fluoranthene (6-OH-B[b]F-9,10-diol) were synthesized and evaluated for tumor-initiating activity at initiation doses of 0.04, 0.12, and 0.4 [mu]mol per mouse. Both of these phenolic dihydrodiols exhibited tumor-initiating activity. 5-OH-B[b]F-9,10-diol was the more potent tumor initiator, inducing a 90% incidence of tumor-bearing mice with an average of 7.50 tumors per mouse at a total initiator dose of 0.4 [mu]mol. [sup 32]P-Postlabeling analysis was employed to evaluate the DNA adducts formed in vivo in mouse skin from both 5- and 6-OH-B[b]F-9,10-diol. HPLC analysis of B[b]F-9,10-diol had identical HPLC retention to the major and one of the minor adducts observed for B[b]F. These two DNA adducts account for 58% of the modified nucleotides detected in mouse skin following the topical application of B[b]F. Methods for the preparation of trans-9,10-dihydroxy-anti-11,12-epoxy-5-hydroxy-9,10,11,12-tetrahydrobenzo[b]fluoranthene (5-OH-B[b]F-9,10-DE) were developed. The DNA adducts formed with 5-OH-B[b]F-9,10-DE were similar to the adducts formed with 5-OH-B[b]F-9,10-diol. The results of the DNA binding studies along with the tumor-initiating data indicate that 5-OH-B[b]F-9,10-diol is the major proximate tumorigenic metabolite of B[b]F on mouse skin. Studies performed with deoxyguanosine 3[prime]-phosphate suggest that the principal adducts formed are the result of the interaction with deoxyguanosine. 33 refs., 5 figs., 1 tab.

• OSTI ID: 7060390
• Journal Information: Chemical Research in Toxicology; (United States), Journal Name: Chemical Research in Toxicology; (United States) Vol. 6:4; ISSN 0893-228X; ISSN CRTOEC
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ANIMALS
AROMATICS
BIOASSAY
BIOSYNTHESIS
BODY
CARCINOGENESIS
DNA ADDUCTS
HYDROCARBONS
MAMMALS
METABOLIC ACTIVATION
MICE
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
POLYCYCLIC AROMATIC HYDROCARBONS
RODENTS
SKIN
SYNTHESIS
VERTEBRATES