Effect of fluorine substitution on benzo[j]fluoranthene genotoxicity.
The metabolism and mutagenic activity of 4-fluorobenzo[j]fluoranthene (4F-B[j]F) and 10-fluorobenzo[j]fluoranthene (10F-B[j]F) were evaluated and compared with benzo[j]fluoranthene (B[j]F) using an identical rat liver homogenate preparation. Previous studies have shown that the major genotoxic metabolites of B[j]F are the 4,5- and 9,10-dihydrodiol. The 9,10-dihydrodiol was the principal metabolite formed in the case of 4F-B[j]F, while the 4,5-dihydrodiol was the principal metabolite formed in the metabolism of 10F-B[j]F. Studies on the relative genotoxicity of these fluorinated derivatives were performed to indirectly determine the possible contribution of the 4,5- and 9,10-dihydrodiol in the activation of B[j]F to a genotoxic agent. In the presence of microsomal activation, both of these fluorinated derivatives of B[j]F were more mutagenic in S. typhimurium TA97a, TA98 and TA100 than B[j]F. However, differences in mutagenic potency were observed between 4F- and 10F-B[j]F. 10F-B[j]F had similar mutagenic potency to 4F-B[j]F in TA97a and TA98 at doses associated with the linear portion of the dose response curve. However, a slightly higher mutagenic response was observed with 10F-B[j]F in TA98 at doses above 5 nmol. In contrast, 4F-B[j]F was more active than 10F-B[j]F as a mutagen in TA100. The tumor-initiating activity of these analogs on mouse skin was assessed at doses of 2.0, 1.0 and 0.3 mumol. Skin irritation was observed with the fluorinated B[j]F derivatives at doses above 0.3 mumol. At a dose of 0.3 mumol, 4F-B[j]F exhibited tumorigenic activity which was similar to B[j]F. In contrast, 10F-B[j]F was less active than B[j]F at all three doses assayed. Both fluorinated derivatives of B[j]F formed higher levels of DNA adducts in vivo in mouse skin than B[j]F. A modified 32P-postlabeling method was required to detect fast migrating B[j]F:DNA adducts that went undetected in previous studies. The level of DNA adducts formed from 4F-B[j]F was considerably greater than the levels observed with 10F-B[j]F. This is consistent with the greater mutagenic activity in S. typhimurium TA100 and tumor-initiating activity exhibited by 4F-B[j]F. These studies suggest that fluorine substitution may significantly alter the intrinsic genotoxicity of the 4,5- and 9,10-dihydrodiol of B[j]F. These data also imply that B[j]F may be primarily activated via the formation of the 9,10-dihydrodiol metabolite. This pathway of activation is inconsistent with our previous studies which indicate that the 4,5-dihydrodiol is the most important pathway of activation.(ABSTRACT TRUNCATED AT 400 WORDS)
Weyand
E H
EH
Rutgers, State University of New Jersey, College of Pharmacy, Piscataway 08855-0789.
He
Z M
ZM
Ghodrati
F
F
Wu
Y
Y
Marshall
M V
MV
LaVoie
E J
EJ
D000818:Animals; D015197:Carcinogenicity Tests; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005449:Fluorenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D005461:Fluorine / Q000737:chemistry*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000378:metabolism; D013329:Structure-Activity Relationship
D005449:Fluorenes; D009153:Mutagens; C076937:4-fluorobenzo(j)fluoranthene; C076906:10-fluorobenzo(j)fluoranthene; C027704:benzo(j)fluoranthene; D005461:Fluorine; D004247:DNA