Dimethylarsinic acid treatment alters six different rat biochemical parameters: relevance to arsenic carcinogenesis.
In a previous study, we found that sodium arsenite increased hepatic ornithine decarboxylase (ODC) activity and hepatic heme oxygenase (HO) activity, but did not cause any DNA damage in adult female rat liver or lung, suggesting that arsenite may be a promoter of carcinogenesis. In this study sodium arsenate, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) were administered orally in equitoxic doses to adult female rats at 21 and 4 h prior to sacrifice. DNA damage (DD), cytochrome P450 content (P450), glutathione content (GSH), ODC, serum alanine aminotransferase (ALT) and HO were measured in liver and/or lung tissue. At 60 mg/kg in rat liver, sodium arsenate increased hepatic HO fivefold. MMA decreased ALT at 226 mg/kg, decreased ALT and GSH at 679 mg/kg and also increased P450 at 679 mg/kg in rat liver. DMA decreased ALT and hepatic GSH and increased hepatic HO at 387 mg/kg. In the lung, DMA decreased ODC at both 129 and 387 mg/kg. DD in lung tissue was significantly higher at 387 mg/kg DMA, demonstrating organ specific DNA damage. The biochemical effects and the inferred oncologic potential of the four major forms of arsenic (arsenate, arsenite, MMA and DMA) differ dramatically. The inorganic forms (arsenate and arsenite) are similar to each other (both good HO inducers); the methylated organic forms of arsenic (MMA and DMA) also share a similar pattern of biochemical effects (decreased GSH and ALT, increased P450). All six of the biochemical parameters studied were altered by DMA in either rat liver or lung.
Brown
J L
JL
Environmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Kitchin
K T
KT
George
M
M
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001149:Arsenates / Q000633:toxicity; D020261:Arsenic Poisoning; D001152:Arsenicals; D014408:Biomarkers, Tumor; D002101:Cacodylic Acid / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D005978:Glutathione / Q000032:analysis; D005982:Glutathione Transferase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001149:Arsenates; D001152:Arsenicals; D014408:Biomarkers, Tumor; D006540:Herbicides; C009277:sodium arsenate; D003577:Cytochrome P-450 Enzyme System; D002101:Cacodylic Acid; D006419:Heme Oxygenase (Decyclizing); D005982:Glutathione Transferase; D000410:Alanine Transaminase; D009955:Ornithine Decarboxylase; D005978:Glutathione; C020300:monomethylarsonic acid