Specificity of heme for hemopoietic recovery from AZT toxicity.
The toxicity of azidothymidine (AZT) was studied on normal human bone marrow hemopoietic colony growth as determined by assays of CFU-E, BFU-E, and CFU-GM. The potential sparing effect of hemin and heme analogues on AZT-suppressed bone marrow was also investigated. AZT at a lower concentration (0.1 mumol/L) inhibited CFU-E by 68%, BFU-E by 84%, and CFU-GM by 59%. AZT at a higher concentration (1.0 mumol/L) inhibited CFU-E by 88%, BFU-E by 90%, and CFU-GM by 69%. Addition of hemin (10 mumol/L) to cultures containing AZT (0.1 mumol/L) increased CFU-E growth by 279%, BFU-E by 282%, and CFU-GM by 72%. A similar concentration of heme analogues did not have an enhancing effect; in contrast, zinc protoporphyrin (ZnPP) was inhibitory to bone marrow progenitors CFU-E, BFU-E, and CFU-GM. In addition, no enhancement of colony growth was obtained when progenitor cells were cultured in the presence of 10(-2)-10(-5) M iron. These results demonstrate that exogenous hemin has a specific beneficial effect on human bone marrow hematopoietic progenitor cells which is not seen with iron or other metalloporphyrins. Furthermore, this beneficial effect includes a reversal of the cytotoxic effect of AZT on bone marrow progenitors.
Loewy
G
G
Cabrini Medical Center, New York, New York 10003.
Cook
P
P
Ahmed
T
T
Lutton
J D
JD
Nishimura
M
M
Distenfeld
A
A
Levere
R D
RD
Abraham
N G
NG
D002455:Cell Division / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006418:Heme / Q000494:pharmacology*; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D012680:Sensitivity and Specificity; D015215:Zidovudine / Q000037:antagonists & inhibitors* / Q000633:toxicity
D011524:Protoporphyrins; D006418:Heme; D015215:Zidovudine; D006427:Hemin; D007501:Iron