Can glutathione‐S‐transferases function as intracellular heme carriers?

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Abstract
The possibility that glutathione‐S‐transferases can serve as heme carriers in cells was studied via the following two characteristics: the ability to bind hemin reversibly and the coordination between heme and glutahione‐S‐transferases level in the cell. Two erythroleukemic cell lines that can be induced to synthesize hemoglobin were studied, K‐562 and Friend murine erythroleukemia cells. It was found that hemin‐associated glutathione‐S‐transferase tends to lose its native structure as expressed by partial irreversible inhibition of glutathione conjugation activity. In K‐562 cells, a small increase in heme synthesis was induced, but under no condition could glutathione‐S‐transferase be elevated. In addition, introduction of high hemin from without caused large hemoglobin production but did not inducechanges in the glutathione‐S‐transferase content. Dimethyl sulfoxide‐induced Friend murine eryth‐roleukemia cells synthesized a large amount of endogenous hemin that had to be transported from the mitochondria for hemoglobin synthesis. Although a concomitant increase in glutathione‐S‐transferase level (20–40%) was observed, it was only short‐lived, unlike hemin, which continued to increase. These data indicate a lack of correlation between glutathione‐S‐transferase and hemin or hemoglobin levels. Finally, dimethyl sulfoxide‐induced cells were treated with succinyl acetone to inhibit heme synthesis. These cells showed the same increased levels and time‐dependent pattern of gluathione‐S‐transferase as untreated cells. A similar phenomenon was observed when different substrates were used to measure the activities of glutathione‐S‐transferases. These results raise doubts about the possibility of glutathione‐S‐transferases functioning as heme carriers in cells.