Abstract
Bergamottin (BM, 1), a component of grapefruit juice, acts as an inhibitor of some isoforms of the cytochrome P450 (CYP) enzyme, particularly CYP3A4. Herein, a new bergamottin containing a nitroxide moiety (SL-bergamottin, SL-BM, 10) was synthesized; chemically characterized, evaluated as a potential inhibitor of the CYP2C19, CYP3A4, and CYP2C9 enzymes; and compared to BM and known inhibitors such as ketoconazole (KET) (3A4), warfarin (WAR) (2C9), and ticlopidine (TIC) (2C19). The antitumor activity of the new SL-bergamottin was also investigated. Among the compounds studied, BM showed the strongest inhibition of the CYP2C9 and 2C19 enzymes. SL-BM is a more potent inhibitor of CYP3A4 than the parent compound; this finding was also supported by docking studies, suggesting that the binding positions of BM and SL-BM to the active site of CYP3A4 are very similar, but that SL-BM had a better ∆Gbind value than that of BM. The nitroxide moiety markedly increased the antitumor activity of BM toward HeLa cells and marginally increased its toxicity toward a normal cell line. In conclusion, modification of the geranyl sidechain of BM can result in new CYP3A4 enzyme inhibitors with strong antitumor effects.
Highlights
Bergamottin (i.e., 5-geranoxypsoralen (1)) is a natural furanocoumarin that was originally detected in bergamot oil (Citrus bergamia) [1] and is mainly responsible, together with 6,7 -dihydroxybergamottin (DHB, 2), for “grapefruit juice/drug” interactions (Figure 1)
Grapefruit juice has been found to cause a marked increase in the oral bioavailability of many therapeutic agents primarily by inhibiting the CYP3A4 enzyme
SL-BM only slightly inhibits CYP2C9 and is almost a 15-fold weaker inhibitor of CYP2C19 than BM (Table 1)
Summary
Bergamottin (i.e., 5-geranoxypsoralen (1)) is a natural furanocoumarin that was originally detected in bergamot oil (Citrus bergamia) [1] and is mainly responsible, together with 6 ,7 -dihydroxybergamottin (DHB, 2), for “grapefruit juice/drug” interactions (Figure 1). Several mechanisms have been reported regarding the CYP3A4 inhibitory effect of bergamottin such as decreased protein expression or the reversible inhibition of the enzyme [7,8,9,10]. Row et al studied the inhibitory effects of a series of furanocoumarin analogues on the CYP3A4 enzyme. They found that the furan ring and the alkyloxy group were necessary for inhibition, and hydrophilic groups at 6 ,7 -positions enhanced the potency compared to the alkenyl group [11]. Bergamottin was found to inhibit CYP2A6, 2C9, 2C19, 2D6, and 2E1 enzymes in human liver microsomes [14]
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