Regulation of cytochrome P4501A metabolism by glutathione

Gene expression of cytochrome P4501A (CYPlA) in the rainbow trout Oncorhync hus mykiss is dependent on aromatic hydrocarbon receptor signal transductio n, and is markedly sensitive to tissue thiol status. Tissue glutathione (GS H) status was manipulated by exogenous GSH, L-buthionine-[S,R]sulfoximine ( BSO), lipoate or 1,3-bis(2-chloroethyl)-2-nitrosourea (BCNU). Tissue GSH co ntents were significantly elevated in GSH- and lipoate-supplemented trout. Hepatic, renal and plasma GSH levels were markedly arrested in BSO-treated trout. Oxidized glutathione (oxidized GSH) levels were significantly elevat ed in the BCNU-supplemented group. Both BCNU treatment and BSO-induced GSH deficiency increased steady-state levels of hepatic CYP1A mRNA. Additional exposure to 0.1 mg/kg 3,3',4,4'-tetrachlorobiphenyl marginally suppressed t he tetrachlorobiphenyl-dependent CYP1A induction in BSO-treated livers comp ared with the respective thiol treatment groups. Tetrachlorobiphenyl exposu res altered efficiencies of thiol treatments and increased oxidized GSH con tent in all but the BSO-treated groups. However, exposure to 5 mg/kg tetrac hlorobiphenyl altered effects of thiol treatments on CYP1A mRNA to a small extent, but catalytic activity of CYP1A was many times suppressed in BSO-tr eated and lipoate-supplemented fish. These results suggest that thiol statu s interferes with CYP1A metabolism in a two-way mode of action and provide further evidence for a cross-talk between cytochrome P4501A and glutathione .