Polycyclic aromatic hydrocarbons in food - Efflux of the conjugated biomarker 1-hydroxypyrene is mediated by Breast Cancer Resistance Protein (ABCG2) in human intestinal Caco-2 cells

- Caco-2 cells metabolize pyrene into 1-OHP which is in turn converted to hydrophilic sulfate and glucuronide conjugates.
- Both pyrene conjugates are mainly excreted apically by an ABCG2/BCRP driven transport over the intestinal Caco-2 monolayer.
- AhR agonists increase the transport rate of pyrene 1-sulfate and 1-glucuronide.
- Sulfonylation of 1-hydroxypyrene is catalyzed by human hSULT1A2 > hSULT1A1 > hSULT1A3 > hSULT1B1.

Polycyclic aromatic hydrocarbons (PAHs) are well-known food contaminants comprising compounds with carcinogenic properties. Pyrene (PYR) is an important non-carcinogenic PAH because its metabolites are frequently used as biomarkers to assess human PAH exposure. This study investigated for the first time the formation and transport of PYR metabolites in the human small intestinal Caco-2 cell model using HPLC technique. The intermediate phase I metabolite 1-hydroxypyrene formed by cytochrome P450 monooxygenases is subsequently conjugated by phase II enzymes to the water-soluble PYR 1-glucuronide as minor and PYR 1-sulfate as major metabolites. The formation of the latter is mediated by human sulfotransferases 1A1∗Arg, 1A2∗1, 1A3, and 1B1. Caco-2 monolayer experiments revealed a predominantly apical transport of both conjugates mediated by the breast cancer resistance protein (BCRP/ABCG2). Additional treatment with several aryl hydrocarbon receptor (AhR) agonists indicate an AhR-driven induction of PYR-metabolizing enzymes and/or ABCG2. Overall, this study provides advanced mechanistic insights into the bioavailability of PYR and underlines a key role of the human small intestinal epithelium for the first pass metabolism of contaminants in food.