Superfund Research Program
The Human Genetics of Arsenic Biotransformation
Project Leader: H. Vasken Aposhian
Grant Number: P42ES004940
Funding Period: 2000-2010
Final Progress Reports
Year: 2009 2004
Over the past funding period, Dr. Aposhian’s laboratory was the first to show that mammals have an arsenate reductase, which is the same protein as purine phosphorylase. Another important finding was methylation of inorganic arsenic is not a detoxification process. Rather, it is the bioactivation of inorganic arsenite to MMAIII and DMAIII which is more toxic than inorganic arsenite and that MMAIII has been found in the urine of individuals exposed to inorganic arsenic. This finding has completely revolutionized how people investigating the toxicology and carcinogenicity of inorganic arsenic now look at and study this major environmental problem. The importance of MMAIII and DMAIII toxicity will be important in risk assessment and in understanding inorganic arsenic carcinogenicity.
Dr. Aposhian has found that human MMA(V) reductase and hGSTO1-11 are identical proteins. This protein is a crucial enzyme in the biotransformation of inorganic arsenic. It catalyzes the reduction of arsenate, MMA(V), and DMA(V). MALDI-TOF and MS/MS analysis demonstrated that five molecules of GSH are bound to one subunit monomer of hGSTO1-1; four of the five cysteines were glutathionylated when GSH was present. Cys-32 in the active center, however, exists mostly in the sulfhydryl. Understanding the mechanism of reduction of arsenic-V species to their more toxic arsenic-III forms is critical for determining how tissues (people) activate arsenic to more toxic forms.