TY - JOUR
T1 - Influence of lipophilicity on the interactions of hydroxy stilbenes with cytochrome P450 3A4
AU - Regev-Shoshani, Gilly
AU - Shoseyov, Oded
AU - Kerem, Zohar
PY - 2004/10/15
Y1 - 2004/10/15
N2 - Resveratrol, a polyphenol found in red wine, was recently suggested to act as an irreversible, mechanism-based inactivator of cytochrome P450 3A4 (CYP3A4). We found a significant inhibition of human CYP3A4-dependent transformation of cyclosporine by resveratrol, with IC 50 = 4.5 μM. We studied the kinetics parameters of CYP3A4 transformation of resveratrol and structurally related, naturally occurring stilbenes. Resveratrol, piceid, resveratroloside, 5,4′-dihydroxy-3-O-methoxystilbene, and 5,3-dihydroxy-4′-O- methoxystilbene were all shown to inhibit hydroxylation of testosterone by CYP3A4. Both methoxy-stilbenes had lower IC 50 values, ranging from 0.43 to 0.47 μM, suggesting that lipophilicity rather than number or positions of free hydroxyls (3,5 or 5,4′) determines the CYP3A4 inhibition capacity of polyphenols. In line with these findings, both glucosyl-stilbenes were found to be weak inhibitors of CYP3A4. The affinity of the enzyme towards methoxy-stilbenes, expressed as apparent K m, was indeed higher than those for the parent resveratrol and its glucosides, in CYP3A4 reaction mixtures. V max values were similar, except for piceid. These results support the role of lipophilicity in the interaction of polyphenols with CYP3A4. It is suggested that selective structural modifications of substrates add significantly to knowledge acquired through molecular modifications of the enzyme.
AB - Resveratrol, a polyphenol found in red wine, was recently suggested to act as an irreversible, mechanism-based inactivator of cytochrome P450 3A4 (CYP3A4). We found a significant inhibition of human CYP3A4-dependent transformation of cyclosporine by resveratrol, with IC 50 = 4.5 μM. We studied the kinetics parameters of CYP3A4 transformation of resveratrol and structurally related, naturally occurring stilbenes. Resveratrol, piceid, resveratroloside, 5,4′-dihydroxy-3-O-methoxystilbene, and 5,3-dihydroxy-4′-O- methoxystilbene were all shown to inhibit hydroxylation of testosterone by CYP3A4. Both methoxy-stilbenes had lower IC 50 values, ranging from 0.43 to 0.47 μM, suggesting that lipophilicity rather than number or positions of free hydroxyls (3,5 or 5,4′) determines the CYP3A4 inhibition capacity of polyphenols. In line with these findings, both glucosyl-stilbenes were found to be weak inhibitors of CYP3A4. The affinity of the enzyme towards methoxy-stilbenes, expressed as apparent K m, was indeed higher than those for the parent resveratrol and its glucosides, in CYP3A4 reaction mixtures. V max values were similar, except for piceid. These results support the role of lipophilicity in the interaction of polyphenols with CYP3A4. It is suggested that selective structural modifications of substrates add significantly to knowledge acquired through molecular modifications of the enzyme.
KW - CYP3A4
KW - Cyclosporine
KW - Kinetics
KW - Piceid
KW - Polyphenols
KW - Resveratrol
UR - http://www.scopus.com/inward/record.url?scp=4544292829&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2004.08.141
DO - 10.1016/j.bbrc.2004.08.141
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C2 - 15369802
AN - SCOPUS:4544292829
SN - 0006-291X
VL - 323
SP - 668
EP - 673
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -