Re: IBD & Dioxins Link?

> Persistent activation of the AhR is probably responsible for toxic
> responses in experimental animals and humans.

Uncoupling-mediated generation of reactive oxygen by halogenated
aromatic hydrocarbons in mouse liver microsomes.
Studying liver microsomes from TCDD-induced or vehicle-treated
(noninduced) mice, we evaluated the in vitro effects of added
chemicals on the production of reactive oxygen due to substrate/P450-
mediated uncoupling. The catalase-inhibited NADPH-dependent H(2)O(2)
production (luminol assay) was lower in induced than noninduced
microsomes. The effects of adding chemicals (2.5 microM) in vitro
could be divided into three categories: Group 1, highly halogenated
and coplanar compounds that increased H(2)O(2) production at least 5-
fold in induced, but not in noninduced, microsomes; Group 2, non-
coplanar halogenated biphenyls that did not affect H(2)O(2)
production; Group 3, minimally halogenated biphenyls and
benzo[a]pyrene that decreased H(2)O(2) production. Molar consumption
of NADPH and O(2) and molar H(2)O(2) production (o-dianisidine
oxidation) revealed that Group 1 compounds mostly increased, Group 2
had no effect, and Group 3 decreased the H(2)O(2)/O(2) and H(2)O(2)/
NADPH ratios. Microsomal lipid peroxidation (thiobarbituric acid-
reactive substances) was pro****tional to H(2)O(2) production. Although
TCDD induction decreased microsomal production of H(2)O(2), addition
of Group 1 compounds to TCDD-induced microsomes in vitro stimulated
the second-electron reduction of cytochrome P450 and subsequent
release of H(2)O(2) production. This pathway is likely to contribute
to the oxidative stress response and associated toxicity produced by
many of these environmental chemicals. PMID: 14980705