Genotoxic activation of benzophenone and its two metabolites by human cytochrome P450s in SOS/umu assay.
The genotoxic potential of benzophenone and its metabolically related compounds, benzhydrol and p-benzoylphenol, was investigated using human cytochrome P450 (P450) enzymes. Benzophenone and its two metabolites (0.1-1mM) showed a suppression of bacterial growth without any P450 system, but no induction of umu gene expression was observed in Salmonella typhimurium TA1535/pSK1002. Human liver microsomes induced the bacterial cytotoxicity of these compounds without any umu gene expression. On the other hand, with the addition of Escherichia coli membranes expressing recombinant human P450 2A6 and NADPH-cytochrome P450 reductase (NPR), benzophenone showed umu gene expression (64 umu units/min/nmol) P450 2A6). Moderate activation of benzophenone by P450 1A1/NPR membranes, 1A2/NPR membranes, or 1B1/NPR membranes was also observed. Activation of benzhydrol and p-benzoylphenol by the P450/NPR system was similar to that of benzophenone. These results suggest that benzophenone and its metabolically related benzhydrol and p-benzoylphenol can be bioactivated by P450 2A6 and P450 family 1 enzymes. Until now, benzophenone has been investigated mainly in terms of estrogenic activity and cytotoxicity, however, the genotoxic activation of benzophenone by human cytochrome P450s should be examined in terms of the risks to humans.
Takemoto
Kei
K
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Japan.
Yamazaki
Hiroshi
H
Nakajima
Miki
M
Yokoi
Tsuyoshi
T
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001559:Benzhydryl Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics; D001577:Benzophenones / Q000009:adverse effects* / Q000493:pharmacokinetics; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity*; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism; D017319:Photosensitizing Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D013014:SOS Response, Genetics; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D001559:Benzhydryl Compounds; D001577:Benzophenones; D002273:Carcinogens; D009153:Mutagens; D017319:Photosensitizing Agents; D011994:Recombinant Proteins; C047723:benzophenone; D003577:Cytochrome P-450 Enzyme System; C031961:4-benzylphenol; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D009251:NADPH-Ferrihemoprotein Reductase; C020225:benzohydrol