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1378695 
Journal Article 
Effect Of An Inactivator Of Glyceraldehyde- 3-Phosphate Dehydrogenase (GAPDH), A Fortuitous Arsenate Reductase, On Disposition Of Arsenate In Rats 
Gregus, Z; Nemeti, B; Csanaky, I 
2006 
1 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
TOX/6000977 
90 
1-S 
eng 
The environmentally prevalent arsenate (AsV) is reduced in the body to the much more toxic arsenite (AsIII). Recently, we have demonstrated that the glycolytic enzyme GAPDH catalyzes the reduction of AsV in presence of glutathione, yet the role of GAPDH in AsV reduction in vivo is unknown. Therefore, we examined the effect of alpha-cholorhydrin (ACH), which forms a GAPDH-inhibitory metabolite, on the reduction of AsV in rats. These studies confirmed the in vitro role of GAPDH as an AsV reductase, inasmuch as 3 hrs after administration of ACH (100 or 200 mg/kg, ip) to rats both the cytosolic GAPDH activity and the AsV-reducing activity dramatically fell in the liver, moderately decreased in the kidneys and remained unchanged in the muscle. Moreover, the AsV reducing activity closely correlated with the GAPDH activity in the hepatic cytosols of control and ACH-treated rats. Some confounding effects of ACH prompted us to examine its influence on the disposition of injected AsV (50 umol/kg, iv) in rats with ligated bile duct as well as in rats with ligated bile duct and renal pedicles. These studies demonstrated that the hepatic retention of AsV significantly increased and the combined levels of AsV metabolites (i.e., AsIII plus methylated arsenicals) in the liver decreased in response to ACH; however, ACH failed to delay the disappearance of AsV from the blood of rats with blocked excretory routes. Thus, the GAPDH inactivator ACH inhibits AsV reduction by the liver, but not by the whole body, probably because the impaired hepatic reduction is compensated for by hepatic and extrahepatic AsV-reducing mechanisms spared by ACH. It is most likely that ACH inhibits hepatic AsV reduction predominantly by inactivating GAPDH in the liver, however, a slight ACH-induced glutathione depletion may also contribute. While this study seems to support the conclusion that GAPDH in the liver is involved in AsV reduction in rats, confirmation of the in vivo role of GAPDH as an AsV reductase is desirable.