Protection against AZT-induced mutagenesis at the HGPRT locus in a human cell line by WR-151326.
The anti-AIDS agent, AZT (3'-azido-3'-deoxythymidine), is mutagenic in a cultured human hepatoma cell line designated HepG2 at the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) locus. Using an exposure time of 3 hr, the number of mutants per 10(6) surviving cells increased as a function of AZT dose from 125 to 520. Chinese hamster ovary cells, in contrast, are not affected with respect to this endpoint when similar concentrations of AZT are used (i.e., 0.1 to 10 mg/ml). The aminothiol WR-151326 [3-(3-methylaminopropylamino) propanethiol dihydrochloride] was evaluated as a possible antimutagen for use with AZT. At a concentration of 4 mM, WR-151326 was added either concomitantly or following exposure of HepG2 cells to a 5 mg/ml concentration of AZT. Regardless of the treatment condition, WR-151326 was effective in reducing the mutagenic effects of AZT by about a factor of 2. Correcting for background mutations, the mutation frequencies determined were: AZT only for 3 hr, 110 x 10(-6) (S.E.M. +/- 6.0 x 10(-6)); AZT together with WR-151326 for 3 hr, 57 x 10(-6) (S.E.M. +/- 3.0 x 10(-6)); and AZT for 3 hr followed by WR-151326 for 3 hr, 68 x 10(-6) (S.E.M. +/- 5.0 x 10(-6)). This study demonstrates that AZT is mutagenic to a cell line of human origin and that WR-151326 can protect against this mutagenic process.
Grdina
D J
DJ
Biological and Medical Research Division, Argonne National Laboratory, IL 60439.
Dale
P
P
Weichselbaum
R
R
D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D066298:In Vitro Techniques; D016296:Mutagenesis / Q000187:drug effects* / Q000235:genetics; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000009:adverse effects*
D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds; C058704:3-(3-methylaminopropylamino)propylmercaptan; D015215:Zidovudine; D007041:Hypoxanthine Phosphoribosyltransferase