Incorporation of radioactivity from labeled Di-(2-ethylhexyl)phthalate into DNA of rat liver in vivo.

Di-(2-ethylhexyl)phthalate (DEHP), when fed at high levels in the diet for two years, is reportedly an hepatocarcinogen to rats and mice. Radioactivity from ethylhexyl-labeled, but not from phthalate-labeled, [14C]-DEHP is associated with highly purified DNA from the livers of treated rats and this radioactivity is not accounted for by assumptions of adsorption, intercalation, attachment to RNA or histones, an impurity in the labeled DEHP, or artifactual binding during sample workup. Spontaneous binding of radioactivity to DNA from either ethylhexyl-labeled DEHP or its total urinary metabolites could not be detected. Although rat liver slices generated all of the known metabolites of DEHP in vitro, no binding to DNA occurred. Administration of dual 3H/14C-labeled DEHP to rats yielded liver DNA whose 3H/14C ratio was inconsistent with the attachment of any reasonable multi-carbon fragment from the ethylhexyl portion to the DNA. The observation that roughly 100 times as high a percentage of the 14C administered was found in urea as in total DNA suggests that the 14C entered DNA through carbamyl phosphate, a precursor of both urea and pyrimidine bases. If this is the case, the association of C-1 from the ethylhexyl portion of DEHP with DNA may not involve alteration of the DNA or genetic damage.