ROLE OF HEME METABOLISM IN AZT-INDUCED BONE-MARROW TOXICITY

We studied the effects of azidothymidine (AZT) on rat bone marrow heme metabolism and colony growth as determined by assays of granulocyte‐macrophage (CFU‐GM), erythroid (CFU‐E), burst‐forming erythroid (BFU‐E), and α‐aminolevulinic acid synthase (ALAS), the first enzyme in the heme pathway. In all cases, AZT (1–0.01 μM) was found to be toxic to bone marrow colony growth. When AZT was included in colony assays, 1 μM resulted in 98–100% inhibition, whereas lower concentrations (0.01 μM) inhibited growth by 58–76%. In addition, cultures from AZT‐treated animals had a marked reduction in colony growth as compared with sham controls. In most cases, hemin (10−5 M) was found to overcome some of the colony inhibitory effects of AZT. Analysis of heme metabolism indicated that ALAS activity was reduced by 71% in bone marrow cells from treated animals. ALAS activity for control was 204 ± 33 pM ALA formed/4 ± 106 cells/hr, whereas ALAS activity from AZT‐treated animals was only 60 ± 3 pM ALA formed/4 ± 106 cells/hr. It is considered that AZT toxicity may be due in part to a depression in the pool of available heme, which is required for adequate hematopoiesis. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company