title: Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4.
abstract: A number of furanocoumarins isolated from grapefruit juice have been found to inhibit CYP3A4 activity in vitro. In this study, we have designed and synthesised a range of analogues based on bergamottin to investigate the relationship between chemical structure and inhibition of CYP3A4 activity. Studies were performed using human liver microsomes and human intestinal S9 fraction, with testosterone as the marker substrate. With the exception of the coumarin and phenolic furanocoumarin derivatives, which were inactive, the alkyloxy-furanocoumarin analogues were found to inhibit CYP3A4 activity in a dose dependent manner, with observed IC50 values ranging from 0.13 +/- 0.03 to 49.3 +/- 1.9 microM. The unsaturated furan derivatives were found to exhibit time-dependent inhibition, showing a 2-, 4- and 14-fold increase in potency for 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin and bergamottin, respectively after a preincubation period of ten minutes. Reduction of the furan moiety resulted in an 11-fold decrease in inhibitory potency, suggesting that this functional group is key to the interaction between these compounds and CYP3A4.
authors.affiliation: Academic Unit of Clinical Pharmacology, Pharmacokinetics and Pharmacogenetics Group, University of Sheffield, M Floor, Royal Hallamshire Hospital, Sheffield, UK S10 2JF.
authors.forename: E C
authors.initials: EC
authors.lastname: Row
authors.forename: S A
authors.initials: SA
authors.lastname: Brown
authors.forename: A V
authors.initials: AV
authors.lastname: Stachulski
authors.forename: M S
authors.initials: MS
authors.lastname: Lennard
mesh_terms: D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007422:Intestines / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D013997:Time Factors
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011564:Furocoumarins; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C068337:bergamottin