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ToxSci Advance Access published online on January 19, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi090
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Toxicological Sciences © Society of Toxicology 2005; all rights reserved.
Received December 2, 2004
Accepted January 12, 2005

Biotransformation and Toxicokinetics

Inhibition of Human and Rat CYP1A2 by TCDD and Dioxin-like Chemicals

DF Staskal 1*, JJ Diliberto 2, MJ DeVito 2, and LS Birnbaum 2

1 UNC Curriculum in Toxicology, US EPA, MD B143-01, 109 TW Alexander Dr., Research Triangle Park, NC 27711
2 US EPA, ORD, NHEERL, ETD, US EPA, MD B143-01, 109 TW Alexander Dr., Research Triangle Park, NC 27711

* To whom correspondence should be addressed.
DF Staskal, E-mail: staskal.daniele{at}epa.gov


  Abstract

Dioxins have been shown to bind and induce rodent CYP1A2, producing a dose-dependent hepatic sequestration in vivo. The induction of CYP1A2 activity has been used as a noninvasive biomarker for human exposure to dioxins; while there is a consistent relationship between exposure and hepatic CYP1A2 induction in rodents, this relationship has only been observed in some of the highest exposed human populations. This may be explained by inhibition of CYP1A2 activity by dioxins as some rodent studies demonstrate that rodent CYP1A2 activity can in fact be inhibited by dioxins in vitro. CYP1A2 activity was examined using a series of dioxins to inhibit human and rat CYP1A2 activity in species-specific CYP1A2 SUPERSOMES using three common CYP1A2 substrates. Methoxyresorufin was a more efficient substrate than acetanalide or caffeine in this in vitro system. Rat and human CYP1A2 enzymatic activity is inhibited by TCDD, PCDD, TCDF, 4-PeCDF, and PCBs 126, 169, 105, 118, and 156 in a concentration-dependent manner. These data demonstrate that the in vitro metabolism of prototype substrates is similar between the rat and human CYP1A2 SUPERSOME preparations and that dioxins inhibit CYP1A2 activity in both species. Because of the potential for inhibition of CYP1A2 activity by TCDD and other dioxins, studies examining CYP1A2 induction in dioxin-exposed populations using these substrates should be viewed cautiously.


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