Metabolism and toxicity of benzophenone in isolated rat hepatocytes and estrogenic activity of its metabolites in MCF-7 cells.
The metabolism and cytotoxicity of benzophenone and estrogenic activity of its metabolites have been studied in freshly isolated rat hepatocytes and cultured MCF-7 human breast cancer cells, respectively. The incubation of hepatocytes with benzophenone (0.25-1.0 mM) elicited a concentration- and time-dependent cell death, accompanied by loss of intracellular ATP and depletion of adenine nucleotide pools. Benzophenone at a low-toxic level (0.25 mM) in the hepatocyte suspensions was converted to benzhydrol, p-hydroxybenzophenone and its sulfate conjugate, without marked loss of cell viability. The amounts of benzhydrol and sulfate conjugate increased with time. In contrast, addition of 2,6-dichloro-4-nitrophenol (an inhibitor of sulfotransferase; 0.1 mM), nontoxic to hepatocytes during the incubation period, enhanced benzophenone-induced cytotoxicity, and this effect was accompanied by a decrease in the formation of sulfate conjugate and increase in the amount of free p-hydroxybenzophenone. In another experiment, MCF-7 cells, estrogen-responsible breast cancer cells were cultured in estradiol free medium and then exposed to 10 nM-500 microM benzophenone or its metabolites for 6 days. Although at higher concentrations all the compounds were toxic, except for benzophenone and benzhydrol, 10-100 microM p-hydroxybenzophenone significantly increased cell proliferation. These results indicate that benzophenone is enzymaticaly converted to benzhydrol, p-hydroxybenzophenone and its sulphate conjugate in rat hepatocytes. Even if there is less free p-hydroxybenzophenone than benzhydrol and sulfate conjugate in hepatocyte suspensions, p-hydroxybenzophenone itself acts as a weak xeno-estrogen on MCF-7 cells.
Nakagawa
Y
Y
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073 Tokyo, Japan. yoshio@tokyo-eiken.go.jp
Suzuki
T
T
Tayama
S
S
D000818:Animals; D001577:Benzophenones / Q000378:metabolism / Q000633:toxicity*; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D001577:Benzophenones; D004967:Estrogens; D009596:Nitrophenols; C015802:2,6-dichloro-4-nitrophenol; C047723:benzophenone