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AN INTEGRATED PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF ARSENITE ACTION 2. HEME OXYGENASE INDUCTION IN MICE
Citation:
Kenyon, E M., L. M. Del Razo, M F. Hughes, AND K T. Kitchin. AN INTEGRATED PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF ARSENITE ACTION 2. HEME OXYGENASE INDUCTION IN MICE. TOXICOLOGY. Elsevier Ireland Limited, Limerick, Ireland, 206(3):389-401, (2005).
Impact/Purpose:
to evaluate the relationship of HO induction to arsenite exposure, tissue concentrations and urinary excretion of inorganic arsenic
Description:
Heme oxygenase (HO) is the rate-limiting enzyme in heme degradation and its activity has a significant impact on intracellular heme pools. Rat studies indicate that HO induction is a sensitive, dose-dependent response to arsenite (AsIII) exposure in both liver and kidney. The objective of this study was to evaluate the relationship of HO induction to arsenite exposure, tissue concentrations and urinary excretion of inorganic arsenic (iAs) as well as its metabolites in mice. Levels of iAs, mono- (MMA) and dimethylated arsenic (DMA) as well as HO activity were determined in liver, lung and kidney over time in female B6C3F1 mice given a single oral dose of 0, 1, 10, 30 or 100 ?mol/kg AsIII . Increased HO activity was a time and dose-dependent response in liver and kidney, but not lung. Activity peaked in the 4-6 hour time range in liver and kidney with the responsiveness in liver being ~2-fold greater than kidney. Thus the lowest observed effect level (LOEL) and no observed effect level (NOEL) in this study for HO induction are 100 mol/kg and 30 mol/kg, respectively. IAs was the predominant form of arsenic (As) in liver at all doses, whereas DMA was the predominant form of As in kidney at all doses. Three- to 4-fold higher levels of iAs were achieved in liver compared to kidney. MMA was the least abundant form of As in liver and kidney, never exceeding more than 20% of the total As present. The concentration of iAs in tissue or urine demonstrated the strongest correlation with HO activity in both liver and kidney. Results of this study suggest that HO induction is a biomarker of effect that is specific for tissue iAs because a high, but nontoxic, acute dose of DMA (5220 ?mol/kg) did not induce HO in mice. Thus, HO induction thus has potential for use as a biomarker of inorganic arsenic internal dose to target tissue and may be used as a tool to further the development of a biologically-based dose response model for As.