ToxSci Advance Access published online on December 5, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj065
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1 From the Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021
* To whom correspondence should be addressed. Photooxidized tryptophan (TRP) in tissue culture medium elicits a transient CYP1 induction response in cultured cells. We show here that exposure of TRP to window sunlight (aTRP) greatly increased the potency, efficacy and duration of CYP1A induction by TRP in primary chick embryo hepatocytes and in vivo. Aqueous TRP exposed to sunlight for 7 days exhibited a 100-fold or greater increase in potency over TRP in medium. The induction response was sustained for at least 48 hr and was comparable in efficacy to 2,3,7,8-tetrachlorodibenzo-p-dioxin. In hepatocytes, increases in mRNAs for CYP1A4 and CYP1A5, chick orthologs of mammalian CYP1A1 and 1A2, preceded increases in CYP1A proteins and enzyme activities, 7-ethoxyresorufin deethylase (EROD) for CYP1A4 and arachidonic acid epoxygenation for CYP1A5, consistent with a transcriptional mechanism. Ah-receptor-dependence was evidenced by aTRP induction of EROD in wild type Hepa1c1c7 cells but not in Ah-receptor defective (c35) mutants. Preparations of aTRP were stable for many months at 4° and were relatively resistant to metabolism by hepatocytes or liver microsomes. Fractionation of aTRP by HPLC analysis coupled with EROD assays showed that aTRP contained multiple photoproducts and CYP1A inducing components, which varied in sensitivity to metabolism by hepatocytes. The previously identified TRP photoproduct, 6-formylindolo[3,2-b]carbazole (FICZ) was one component, but FICZ was not required for CYP1A induction by the aTRP mixture. These findings identify the indoor environment and window sunlight in particular, as a new source of CYP1A inducers. Further, the evidence that biologically active metabolites of an endogenous substrate, arachidonic acid, are formed by aTRP-induced CYP1A provides a pathway by which TRP photoproducts, like toxic xenobiotics, could have significant physiologic effects.
Received August 17, 2005
Accepted November 17, 2005
Environmental Toxicology
Sunlight Generates Multiple Tryptophan Photoproducts Eliciting High Efficacy CYP1A Induction in Chick Hepatocytes And IN VIVO
Silvia Diani-Moore 1,
Erin Labitzke 1,
Richard Brown 1,
Alexander Garvin 1,
Linda Wong 1,
and
Arleen B. Rifkind 1 *
Arleen B. Rifkind, E-mail: arifkind{at}med.cornell.edu
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