Bioactivation of hexachlorobutadiene by glutathione conjugation

Abstract

Glutathione (GSH) conjugation reactions in the metabolism of hexachlorobutadiene (HCBD), in rats and mice, initiate a series of metabolic events resulting in the formation of reactive intermediates in the proximal tubular cells of the kidney. The GSH S-conjugate 1-(glutathion-S-yl)-1,2,3,4,4-pentachlorobutadiene (GPCB), which is formed by conjugation of HCBD with GSH in the liver, is not reactive and is eliminated from the liver in the bile or plasma, or both. GPCB may be translocated intact to the kidney and processed there by gamma-glutamyl transpeptidase and dipeptidases to the corresponding cysteine S-conjugate. Alternatively, gamma-glutamyl transpeptidase and dipeptidases present in epithelial cells of the bile duct and small intestine may catalyse the conversion of GPCB to cysteine S-conjugates. The kidney concentrates both GSH and cysteine S-conjugates and processes GSH conjugates to cysteine S-conjugates. A substantial fraction of HCBD cysteine S-conjugate thus concentrated in the kidney is metabolized by renal cysteine conjugate beta-lyase to reactive intermediates. The selective formation of reactive intermediates in the kidney most likely accounts for the organ-specific effects of HCBD. Alternatively, cysteine S-conjugates may be acetylated to yield excretable mercapturic acids.