Formation of DNA and hemoglobin adducts of fluoranthene after single and multiple exposures.
The dose-dependence of hemoglobin binding as well as distribution of fluoranthene and fluoranthene-DNA adducts in various tissues was characterized in male rats 24 h after a single i.p. injection of [3H]fluoranthene. Formation and distribution of DNA adducts after chronic administration of fluoranthene in the diet was also studied. Fluoranthene-derived radioactivity was widely distributed throughout the animal after a single dose, and excreta contained the greatest amounts of radioactivity at all dose levels. Fluoranthene binding to globin was proportional to dose over the range of 2 nmol/kg to 177 mumol/kg, and the adducted protein was cleared at the same rate as unmodified hemoglobin, indicating that the adducts are stable in vivo. In contrast, fluoranthene-DNA adducts were not present at detectable levels in liver or kidney 24 h after one dose; low levels of adducts were found only in the lung at the highest dose level. Chronic administration of fluoranthene in the diet, however, resulted in DNA adduct formation in most tissues examined, including liver, kidney, lung, small intestine, heart, spleen and lymphocytes; adducts were not detectable in testes DNA. The major fluoranthene-DNA adduct found in rat tissues was identified by its chromatographic similarity to the major fluoranthene adduct formed in vitro using microsomally-activated fluoranthene and calf thymus DNA, previously identified as a reaction product of anti-2,3-dihydroxy-1,10b-epoxy-1,2,3-trihydro-fluoranthene with N2-deoxyguanosine. The unusual stability of this diol epoxide at physiological pH may allow transport of this ultimate DNA-binding metabolite to virtually all tissues. These results demonstrate the applicability of the HPLC-32P-postlabelling procedure to detect and quantify fluoranthene-DNA adducts formed in vivo, and suggest that analysis of these adducts in accessible tissues such as lymphocytes may be a means of assessing chronic, high level exposure to fluoranthene. Our results also indicate that hemoglobin adducts of fluoranthene could be useful dosimeters for detecting short-term or chronic exposure to this compound if a suitable method for their detection were developed.
Gorelick
N J
NJ
Toxicology Program, Whitaker College, Cambridge, MA.
Hutchins
D A
DA
Tannenbaum
S R
SR
Wogan
G N
GN
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D006454:Hemoglobins / Q000378:metabolism*; D008297:Male; D010761:Phosphorus Radioisotopes; D011865:Radioisotope Dilution Technique; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014316:Tritium
D005449:Fluorenes; D006454:Hemoglobins; D010761:Phosphorus Radioisotopes; D014316:Tritium; C007738:fluoranthene; D004247:DNA