Adduction of hemoglobin and albumin in vivo by metabolites of trichloroethylene, trichloroacetate, and dichloroacetate in rats and mice.
Adducts to macromolecules from trichloroethylene formed by in vivo and in vitro metabolism have been reported by many investigators. We examined the in vivo adduction of the blood proteins hemoglobin (Hb) and albumin in rats and mice dosed orally with [14C]trichloroethylene ([14C]TRI) to explore the development of a protein adduct biomarker of TRI exposure. We also examined the adduction of these two proteins from doses of [14C]trichloroacetate (TCA) and [14C]dichloroacetate (DCA), two metabolites of TRI. Association of label with albumin peaked at 4-8 hr in the rat (2480 nmol eq TRI/mg protein) and 2-4 hr in the mouse (1580 nmol eq TRI/mg protein). The decay was exponential with a half-life consistent with that of rat or mouse albumin (approx 24 hr). The time course of label with Hb was characterized by an early plateau at 8 hr in rat (28 nmol eq TRI/mg protein), 4 hr in mouse (7 nmol eq TRI/mg protein), and followed by a slow steady increase, peaking at 120 hr (54 nmol eq TRI/mg protein, rat; 38 nmol eq TRI/mg protein, mouse). This apparent binding was linear with dose in the rat, but was convex in the mouse albumin (mouse Hb label was below detection at low dose). We also found that a portion of the irreversibly associated label, referred to by previous investigators as "binding," could be accounted for as metabolic incorporation of label into glycine and serine.(ABSTRACT TRUNCATED AT 250 WORDS)
Stevens
D K
DK
Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman 99164.
Eyre
R J
RJ
Bull
R J
RJ
D000418:Albumins / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002852:Chromatography, Ion Exchange; D003999:Dichloroacetic Acid / Q000097:blood* / Q000493:pharmacokinetics; D006207:Half-Life; D006454:Hemoglobins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014238:Trichloroacetic Acid / Q000097:blood* / Q000493:pharmacokinetics; D014241:Trichloroethylene / Q000097:blood* / Q000493:pharmacokinetics
D000418:Albumins; D000596:Amino Acids; D006454:Hemoglobins; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid