An integrated pharmacokinetic and pharmacodynamic study of arsenite action. 1. Heme oxygenase induction in rats.
Rat heme oxygenase (HO) activity was used as a specific (among forms of arsenic) and sensitive biomarker of effect for orally administered sodium arsenite in rats. Time course studies showed that HO was induced in rat liver from 2 to 48 h in both rat liver and kidney. Hepatic and renal inorganic arsenic (iAs) concentrations were high at times preceding a high degree of HO induction. At times following pronounced HO induction, tissue dimethylarsinic acid concentrations were high. Dose-response studies of arsenite showed substantial HO induction in liver at doses of 30 micromol/kg and higher and in the kidney at doses of 100 micromol/kg and higher. Doses of 10 (in liver) and of 30 micromol/kg (in kidney) sodium arsenite given by gavage did not significantly induce rat HO activity. Speciation of tissue total arsenic into iAs, methylarsonic acid (MMA), and dimethylarsinic acid (DMA) permits us to link tissue iAs and HO enzyme induction. There was a linear relationship between tissue inorganic arsenic (iAs) concentration and tissue HO in individual rats (r(2) = 0.780 in liver and r(2) = 0.797 in kidney). Nonlinear relationships were observed between administered arsenite dose and either liver or kidney iAs concentration. Overall, there was a sublinear relationship between administered arsenite and biological effect in rats. Teratogenesis Carcinog. Mutagen. 19:385-402, 1999. Published 1999 Wiley-Liss, Inc.
Kitchin
K T
KT
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. kitchin.kirk@epamail.epa.gov
Del Razo
L M
LM
Brown
J L
JL
Anderson
W L
WL
Kenyon
E M
EM
D000284:Administration, Oral; D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics; D018053:Arsenites / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001711:Biotransformation; D002101:Cacodylic Acid / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
D018053:Arsenites; D013723:Teratogens; D002101:Cacodylic Acid; D006419:Heme Oxygenase (Decyclizing); C015001:arsenite; D001151:Arsenic