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Role of heme metabolism in AZT‐induced bone marrow toxicity
Author(s) -
Lutton J. D.,
Mathew A.,
Levere R. D.,
Abraham N. G.
Publication year - 1990
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.2830350102
Subject(s) - hemin , heme , toxicity , bone marrow , haematopoiesis , metabolism , zidovudine , biology , pharmacology , medicine , enzyme , endocrinology , chemistry , biochemistry , immunology , stem cell , virus , viral disease , microbiology and biotechnology
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 ± 10 6 cells/hr, whereas ALAS activity from AZT‐treated animals was only 60 ± 3 pM ALA formed/4 ± 10 6 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.