Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice

doi:10.1016/0024-3205(96)00417-1

Life Sciences

Volume 59, Issue 13, 23 August 1996, Pages 1025-1030

https://doi.org/10.1016/0024-3205(96)00417-1 Get rights and content

Abstract

The effect of various citrus juices and solutions of naringin on CYP3A activity in rat liver microsomes was compared by measuring the formation of 6β- hydroxytestosterone from testosterone. Control enzyme activity was reduced by more than 70% by grapefruit juice. Freshly-squeezed sour (Seville) orange juice containing 20% as much naringin was comparable to grapefruit juice in its ability to inhibit microsomal activity. An aqueous solution of naringin at the same concentration as in grapefruit juice produced only a small decrease in 6β-hydroxytestosterone formation. Dilution of grapefruit juice with a naringin solution reduced the inhibitory activity of the juice even though naringin concentration did not change. Naringenin did not form under the incubation conditions used indicating that it did not contribute to the inhibition produced by grapefruit juice. Finally, organic extracts of grapefruit juice possessed considerable inhibitory activity even though naringin was not extractable. These data suggest that grapefruit juice inhibits CYP3A activity $in vitro$ and that neither naringin nor naringenin are primarily responsible for this effect. A compound present in both grapefruit juice and Seville orange juice and extractable into organic solvents appears to be responsible.

References (19)

G.C. Yee et al.
Lancet
(1995)
D.G. Bailey et al.
Lancet
(1991)
P. Mouly et al.
J. Chrom.
(1993)
A.J. Sonderfan et al.
Arch. Biochem. Biophys.
(1987)
M. Daujat et al.
Meth. Enzymol.
(1991)
M.H. Siess et al.
Toxicol. Appl. Pharmacol.
(1995)
M.P. Ducharme et al.
Clin.Pharmacol.Ther.
(1995)
P.A. Soons et al.
Clin. Pharmacol. Ther.
(1991)
H.H.T. Kupferschmidt et al.
Clin. Pharmacol. Ther.
(1995)

There are more references available in the full text version of this article.

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Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice

Abstract

Lancet

Lancet

J. Chrom.

Arch. Biochem. Biophys.

Meth. Enzymol.

Toxicol. Appl. Pharmacol.

Clin.Pharmacol.Ther.

Clin. Pharmacol. Ther.

Clin. Pharmacol. Ther.