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 ars enic) and sensitive biomarker of effect for orally administered sodium arse nite in rats. Time course studies showed that HO was induced in rat liver f rom 2 to 48 h in both rat liver and kidney. Hepatic and renal inorganic ars enic (iAs) concentrations were high at times preceding a high degree of HO induction. At times following pronounced HO induction, tissue dimethylarsin ic acid concentrations were high. Dose-response studies of arsenite showed substantial HO induction in liver at doses of 30 mu mol/kg and higher and i n the kidney at doses of 100 mu mol/kg and higher. Doses of 10 (in liver) a nd of 30 mu mol/kg (in kidney) sodium arsenite given by gavage did not sign ificantly induce rat HO activity. Speciation of tissue total arsenic into i As, methylarsonic acid (MMA), and dimethylarsinic acid (DMA) permits us to link tissue iAs and HO enzyme induction. There was a linear relationship be tween tissue inorganic arsenic (iAs) concentration and tissue HO in individ ual rats (r(2) = 0.780 in liver and r(2) = 0.797 in kidney). Nonlinear rela tionships were observed between administered arsenite dose and either liver or kidney iAs concentration. Overall, there was a sublinear relationship b etween administered arsenite and biological effect in rats. Published 1999 Wiley-Liss, Inc.(dagger).