INHIBITION OF CYP1A1 AND CYP1B1 ENZYMES BY AROMATIC COMPOUNDS ADSORBED ON URBAN DUST PARTICULATE MATTER

Abstract

Recent studies have shown urban dust particulate matter (UDPM) to decrease PAH-DNA adduct levels and cytochrome P450 (CYP) metabolic capacity in human mammary epithelial cell lines. The present study was designed to further elucidate the biochemical mechanisms involved in this inhibition process. We examined the effects of UDPM and its aromatic components on the metabolizing activities of human CYP1A1 and CYP1B1 enzymes as analyzed by the 7-ethoxyresorufin O-deethylation (EROD) assay. The data obtained indicate that the aromatic component of UDPM, derived from a neutral aromatic fraction of dichloromethane extract, inhibited the activity of CYP (no change in K _M, decrease in k _cat /K _M ). Taken together, the decreases in the tumor initiating activity, PAH-DNA adduct formation and CYP1A1 and CYP1B1 activity by UDPM observed in vivo can be attributed to a noncompetitive inhibitory mechanism by the PAH component. Therefore, PAHs within a complex mixture could inhibit CYP metabolic capacity, thereby decreasing the activation of carcinogenic PAH within complex mixtures.

Keywords:

• Polycyclic aromatic hydrocarbons
• urban air pollution
• particulate matter
• cytochrome P450
• chemical inhibition

ACKNOWLEDGEMENTS

We wish to thank Dr. Brinda Mahadevan for critical review of this manuscript. This work was supported by CA28825, Department of Health and Human Services, from the National Cancer Institute, the National Institute of Environmental Health and Safety Pre-doctoral Training Grant supported L.A.C. (T32 ES007060), and the Czech Ministry of Agriculture, MZE 0002716201.

Notes

^a EROD activities were determined at substrate concentrations between 0.05 and 1.25 μ M, and kinetic parameters were determined. Results are present as ± SE estimated for k _cat and K _M (from GraphPad Prism).

^a EROD activities were determined at substrate concentrations between 0.05 and 1.25 μ M, and kinetic parameters were determined. Results are present as ± SE estimated for k _cat and K _M (from GraphPad Prism)