Adduction of Hemoglobin and Albuminin Vivoby Metabolites of Trichloroethylene, Trichloroacetate, and Dichloroacetate in Rats and Mice1

摘要

Adducts to macromolecules from trichloroethylene formed byin vivoandin vitrometabolism have been reported by many investigators. We examined thein vivoadduction of the blood proteins hemoglobin (Hb) and albumin in rats and mice dosed orally with 14Ctrichloroethylene (14CTRI) to explore the development of a protein adduct biomarker of TRI exposure. We also examined the adduction of these two proteins from doses of 14Ctrichloroacetate (TCA) and 14Cdichloroacetate (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. The fraction accounted for by metabolic incorporation was constant in albumin (approximately ), while in Hb, this portion was time dependent, approximately 30at the early sampling time, 75at the late time, implying the observed late increase could be accounted for by metabolic incorporation. TCA and DCA also formed Hb and albumin adducts. Portions of this binding was also due to metabolic incorporation. The pattern of the binding from TCA in albumin was different from that of TRI, implying a route to adduct from TRI which does not proceed thro