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Drug Metabolism and Disposition Fast Forward
First published on June 21, 2006; DOI: 10.1124/dmd.106.010439

0090-9556/06/3409-1606-1614$20.00
DMD 34:1606-1614, 2006

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Inhibition of the Human Liver Microsomal and Human Cytochrome P450 1A2 and 3A4 Metabolism of Estradiol by Deployment-Related and Other Chemicals

Khawja A. Usmani, Taehyeon M. Cho, Randy L. Rose1, and Ernest Hodgson

Arena Pharmaceuticals, Inc., San Diego, California (K.A.U.); and Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina (T.M.C., R.L.R., E.H.)

Cytochromes P450 (P450s) are major catalysts in the metabolism of xenobiotics and endogenous substrates such as estradiol (E2). It has previously been shown that E2 is predominantly metabolized in humans by CYP1A2 and CYP3A4 with 2-hydroxyestradiol (2-OHE2) the major metabolite. This study examines effects of deployment-related and other chemicals on E2 metabolism by human liver microsomes (HLM) and individual P450 isoforms. Kinetic studies using HLM, CYP3A4, and CYP1A2 showed similar affinities (Km) for E2 with respect to 2-OHE2 production. Vmax and CLint values for HLM are 0.32 nmol/min/mg protein and 7.5 µl/min/mg protein; those for CYP3A4 are 6.9 nmol/min/nmol P450 and 291 µl/min/nmol P450; and those for CYP1A2 are 17.4 nmol/min/nmol P450 and 633 µl/min/nmol P450. Phenotyped HLM use showed that individuals with high levels of CYP1A2 and CYP3A4 have the greatest potential to metabolize E2. Preincubation of HLM with a variety of chemicals, including those used in military deployments, resulted in varying levels of inhibition of E2 metabolism. The greatest inhibition was observed with organophosphorus compounds, including chlorpyrifos and fonofos, with up to 80% inhibition for 2-OHE2 production. Carbaryl, a carbamate pesticide, and naphthalene, a jet fuel component, inhibited ca. 40% of E2 metabolism. Preincubation of CYP1A2 with chlorpyrifos, fonofos, carbaryl, or naphthalene resulted in 96, 59, 84, and 87% inhibition of E2 metabolism, respectively. Preincubation of CYP3A4 with chlorpyrifos, fonofos, deltamethrin, or permethrin resulted in 94, 87, 58, and 37% inhibition of E2 metabolism. Chlorpyrifos inhibition of E2 metabolism is shown to be irreversible.

Address correspondence to: Ernest Hodgson, Department of Environmental and Molecular Toxicology, Box 7633, North Carolina State University, Raleigh, NC 27695. E-mail: ernest_hodgson{at}ncsu.edu




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