RT Journal Article
SR Electronic
T1 Blockage of Multidrug Resistance-Associated Proteins Potentiates the Inhibitory Effects of Arsenic Trioxide on CYP1A1 Induction by Polycyclic Aromatic Hydrocarbons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 145
OP 155
DO 10.1124/jpet.102.042176
VO 304
IS 1
A1 Laurent Vernhet
A1 Nathalie Allain
A1 Marc Le Vée
A1 Fabrice Morel
A1 André Guillouzo
A1 Olivier Fardel
YR 2003
UL http://jpet.aspetjournals.org/content/304/1/145.abstract
AB Arsenic is a toxic metalloid known to interact with drug-metabolizing enzymes. In the present study, we investigated the effects of arsenic trioxide (As2O3), recently used as an anticancer drug, on the expression of human cytochrome P450 (P450) 1A1, which bioactivates polycyclic aromatic hydrocarbons into mutagenic metabolites. Clinically relevant concentrations (0.25–5 μM) of As2O3 were demonstrated to inhibit CYP1A activity in primary human hepatocytes and hepatoma Hep3B and HepG2 cells coexposed to 3-methylcholanthrene (3MC), benzo(a)pyrene, or dioxin and the metalloid for 24 h. Inhibition reached 50 and 90% in Hep3B cells treated with 1 and 5 μM As2O3, respectively, and was not due to direct interaction of the metalloid with CYP1A1. As2O3 (2.5–5 μM) was demonstrated to markedly reduce induction of CYP1A1 mRNA and apoprotein levels and gene promotor activity in 3MC-treated Hep3B cells, whereas lower concentrations (0.25–1 μM) were ineffective. These effects of As2O3 were abrogated byN-acetylcysteine. Surprisingly, this agent was found 1) to block cellular arsenic uptake when coincubated with the metalloid and 2) to increase arsenic efflux through multidrug resistance-associated proteins. In addition, blockade of these transporters was shown to enhance intracellular amounts of metalloid and to potentiate its effects on CYP1A1 gene. Finally, our results have demonstrated that As2O3, at low concentrations routinely reached in As2O3-treated patients, prevents induction of human CYP1A1 gene expression and that such an effect is increased by blocking multidrug resistance-associated proteins. The American Society for Pharmacology and Experimental Therapeutics