Induction of cytochrome P450 1B1 in MDA-MB-231 human breast cancer cells by non- ortho-substituted polychlorinated biphenyls

Abstract

The effects of 12 non- ortho-substituted polychlorinated biphenyl (PCB) congeners on the induction of human cytochrome P450 1B1 (CYP1B1), an estradiol 4-hydroxylase, were investigated in MDA-MB-231 breast cancer cells. Three independent quantitative assays were used, in which the rates of estrogen metabolism, the levels of the CYP1B1 and CYP1A1 mRNAs, and luciferase activities under the control of the CYP1B1 promoter were measured. Of the congeners investigated, 3,4,4′,5-tetrachlorobiphenyl (PCB 81), 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), 3,4′,5-trichlorobiphenyl (PCB 39) and 3,3′,4,5-tetrachlorobiphenyl (PCB 78) were the most potent in each assay, causing four to 10-fold increases in response. Exposure to 3,3′,4,4′,5,5′-hexachlorobiphenyl (PCB 169) resulted in elevated CYP1B1 mRNA and increased CYP1B1-promoter driven luciferase activity, but caused depressed rather than elevated rates of E 2 metabolism due to inhibition of CYP1B1. The relative magnitudes of CYP1B1 induction by the PCB congeners, as determined by the three assays, were in close agreement, with the exception noted for PCB 169. These results indicate that PCB structure–activity relationships for the induction of human CYP1B1 are similar to those observed for human CYP1A1, but differ somewhat from what has been reported for induction of rat CYP1A1.