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Metabolism of 2-hydroxy-4-methoxybenzophenone in Isolated Rat Hepatocytes and Xenoestrogenic Effects of Its Metabolites on MCF-7 Human Breast Cancer Cells

Metabolism of 2-hydroxy-4-methoxybenzophenone in Isolated Rat Hepatocytes and Xenoestrogenic Effects of Its Metabolites on MCF-7 Human Breast Cancer Cells

Yoshio Nakagawa, Toshinari Suzuki

Chem Biol Interact. 2002 Feb 20;139(2):115-28.

PMID: 11823001

Abstract:

The metabolism and cytotoxicity of 2-hydroxy-4-methoxybenzophenone (HMB) in isolated rat hepatocytes and the xenoestrogenic activity of HMB and its metabolites in MCF-7 human breast cancer cells and an estrogen receptor competitive binding assay have been studied, respectively. The incubation of hepatocytes with HMB caused a concentration- and time-dependent decrease in cell viability, accompanied by loss of intracellular ATP and adenine nucleotide pools. HMB at a low-toxic level (0.25 mM) in the hepatocyte suspensions was converted enzymatically to 2,4-dihydroxybenzophenone (DHB) and a hydroxylated intermediate, which was tentatively identified as an isomer of 2,2prime prime or minute-dihydroxy-4-methoxybenzophenone (DHMB) as determined by mass spectroscopy coupled with HPLC. Furthermore, the parent compound and both intermediates were rapidly conjugated to glucuronides, whereas free unconjugated DHMB and 2,3,4-trihydroxybenzophenone (THB) were identified as trace intermediates. In another experiment, DHB and THB displaced competitively 17beta-estradiol bound to the recombinant human estrogen receptor alpha in a concentration-dependent manner: IC(50) of diethylstilbestrol and bisphenol A, which are known xenoestorogenic compounds, and DHB and THB was approximately 1 x 10(-8), 1 x 10(-5), 5 x 10(-5) and 5 x 10(-4) M, respectively. Further, DHB at concentrations from 10(-8) to 10(-6) M caused a concentration-dependent proliferation of MCF-7 cells. DHMB and THB at 10(-7) and 10(-6) M also elicited a slight increase in cell numbers, whereas HMB at concentrations from 10(-9) to 10(-4) M did not affect the cell proliferation. Based on the relative IC50 for the competitive binding and the proliferative effect on MCF-7 cells, it follows that in estrogenic potency, DHB>THB>DHMB. These results indicate that some hydroxylated intermediates such as DHB rather than the parent compound act as a xenoestrogen via biotransformation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP131577-A	2-Hydroxy-4-methoxybenzophenone		131-57-7	Price

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