Reversal ofBenzene - induced Inhibition of Reticulocyte Protein Synthesis

Benzene (0.056-0.1 1 3 M) rapidly and synthesis in rabbit reticulocytes while reversibly inhibited protein synthesis in neither ATP nor GSH levels were altered. anucleate human sickle cell and rabbit A translational repressor (HCR) of rereticulocytes. Hemin (50 sM) both preticulocyte cell-free protein synthesis was vented and reversed this effect of benzene. isolated from intact cells incubated with The inhibition in rabbit reticulocytes was benzene, while no signifIcant amount of accompanied by a conversion of polyriboHCR was found in cells incubated with somes to monoribosomes. The polyriboboth benzene and hemin. These results somal disaggregation required ribosomal indicated that benzene inhibits translamovement along mRNA and was also tion at the heme-dependent site of initiaprevented and reversed by 50 MM hemin. tion. The clinical implications of these Benzene was also shown to inhibit heme experiments remain to be elucidated. B ENZENE HAS LONG been implicated as having hematologic toxicity. Although many different toxic manifestations (myeloid metaplasia, lymphopenia, acute myeloblastic leukemia, hemolytic anemia) have been described, the most common finding has been pancytopenia) In mice, suppression of DNA synthesis of differentiated bone marrow cells has been implicated in the etiology of benzene toxicity.2 On the other hand, it has also been reported that the incorporation of radioactive iron into mouse bone marrow is decreased after a single subcutaneous injection of benzene.3 This experiment raises the question of whether or not benzene could directly effect heme synthesis. Hemin has been shown to be required by both intact reticulocytes4’#{176} and their cell-free preparations for maximal globin synthesis.’#{176}’6 When intact cells are rendered hemin deficient, the polyribosomes are converted to single ribosomes at the same time protein synthesis is inhibited.510 This finding indicates that hemin control is at the site of initiation of protein synthesis. Hemin prevents and reverses this inhibition of initiation in the intact cell.’#{176} When cellfree preparations are incubated without hemin a hemin-controlled translational repressor (HCR) ofglobin chain initiation has been shown to form in the postribosomal supernatant at the same time globin synthesis stops.’72#{176} Similar HCR may be isolated from intact erythrocytes that have lost protein synthetic capability,2’ suggesting that HCR is a physiologic regulator ofglobin synthesis. Tryfiates22 has reported that benzene inhibits rat liver protein synthesis