BINDING OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD), 3-METHYLCHOLANTHRE. (MC), AND BENZO(A)PYRENE (BP) TO MOLYBDATE STABLIZED HUMAN PLACENTAL Ah RECEPTOR

Abstract

Induction of human cytochrome P1-450 by environmental pollutants is variable and may affect toxicity of many xenobiotics. This response to chemical exposures is genetically regulated in humans, but the mechanisms are poorly understood. In animals, a specific protein, the Ah receptor, regulates P1-450 induction by substrate binding and nuclear interactions analogous to those of steroid hormone receptors. Previous efforts to identify a similar protein in human tissues have produced eqivocal results. We now report that human placenta, an organ with P1-450 remarkably sensitive to maternal environmental exposures, contains Ah receptor. In the presence of 10 to 20 mM sodium molybdate, we consistently detected protein sedimenting at 9S on sucrose density gradients that specificallly bound TCDD, MC and BP in order of decreasing affinity. This binding was highly specific for known P1-450 inducers and no competition by steroid hormones could be detected. Binding affinities (Kd) were lower in placental preparations (15 nM) than in material from rodents (1-3 nM). Mean Ah receptor level in 10 placentas was 106 ± 13 fmol/mg cytosol protein in the presence of molybdate, but significantly lower (34 ± 6 fmol/mg protein) in its absence (p <0.001). These results demonstrate that human placenta contains high concentrations of Ah receptor and suggest that P1-450 induction in humans is regulated by mechanisms similar to those established for laboratory animals.