Increased mutant frequencies in the HPRT gene locu

Authors: KC Zheng J C Yalowich V E Kagan P Keohavong

Publish Date: 2006/07/11

Volume: 22, Issue: 5, Pages: 361-370

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Abstract

Succinyl acetone SA was initially identified in the urine of patients with tyrosinemia type I an autosomally recessive inherited disease SA has been used to downregulate the activity of myeloperoxidase MPO through its specific inhibition of heme biosynthesis and to investigate the biological properties of MPO in the human myeloid leukemic HL60 cell line The goal of this study is to evaluate the mutagenic potential of SA by determining the frequencies of somatic mutations in the hypoxanthineguanine phosphoribosyl transferase HPRT reporter gene in HL60 cells following treatment with the chemical Treatments of HL60 cells with 500 μmol/L SA for 72 h a condition generally used to inhibit the MPO activity resulted in a significantly increased HPRT mutant frequency HPRTMf compared with the control of untreated cells 4725 × 106 versus 75 × 106 respectively p 001 Treatment of the cells with lower doses of SA also led to an increase in HPRTMf but this was significant only with 200 μmol/L 2867 × 106 p005 and not with doses lower than 100 μmol/L p005 compared with the control of untreated cells 75 × 106 These data show a dose–response increase in HPRTMf in HL60 cells treated with SA suggesting that this chemical causes mutations in the HPRT locus in these cells either directly or indirectly through its inhibition of the MPO activity

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