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 alpha-aminolevulinic acid synthase (ALAS), the first enzyme in the heme pathway. In all cases, AZT (1-0.01 microM) was found to be toxic to bone marrow colony growth. When AZT was included in colony assays, 1 microM resulted in 98-100% inhibition, whereas lower concentrations (0.01 microM) 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 X 10(6) cells/hr, whereas ALAS activity from AZT-treated animals was only 60 +/- 3 pM ALA formed/4 x 10(6) cells/hr. It is considered that AZT toxicity may be due to a depression in the pool of available heme, which is required for adequate hematopoiesis.
Lutton
J D
JD
Department of Medicine, New York Medical College, Valhalla 10595.
Mathew
A
A
Levere
R D
RD
Abraham
N G
NG
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D013234:Stem Cells / Q000187:drug effects; D015215:Zidovudine / Q000506:poisoning*
D006418:Heme; D015215:Zidovudine; D006427:Hemin; D000624:5-Aminolevulinate Synthetase