Abstract:
:Several furanocoumarins were tested for their ability to inhibit human P450 2A6 activity. The metabolites and conjugates formed from these furanocoumarins after incubation with reconstituted purified P450 2A6 in the absence and presence of exogenous nucleophiles were characterized by UV and LC/ESI-MS/MS analysis. The results suggest initial oxidation to form a furanoepoxide followed by hydrolytic attack, or attack of exogenous nucleophiles, to form dihydrofuranocoumarin products. Initial epoxidation is confirmed by the finding that a single 18O atom is incorporated into the 8-methoxypsoralen (8-MOP) and psoralen (P) dihydrodiol metabolites when the incubations are performed in the presence of H218O. In contrast, 19% of the dihydrodiol formed from 5-methoxypsoralen (5-MOP) involves incorporation of two 18O atoms, implicating a gamma-ketoenal intermediate in the formation of this metabolite. Thus, the structure of the reactive intermediate(s) formed is dictated by the intrinsic electronic properties of the parent compound. After exposure to [14C]-8-MOP and [14C]-5-MOP, SDS-PAGE and HPLC experiments, followed by radiometric detection, indicated that both P450 2A6 and P450 reductase were covalently modified in the purified system. In contrast, only P450 2A6 was covalently modified in a lymphablastoid cell line (GENTEST). With the purified system, partition ratios were higher (1.5-3.9X), and the ability to scavenge reactive intermediates with exogenous nucleophiles was greater. These results suggest that relative to the cell system, more reactive intermediates can escape, rather than bind to, the active site of purified reconstituted P450 2A6.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Koenigs LL,Trager WFdoi
10.1021/bi980003csubject
Has Abstractpub_date
1998-07-14 00:00:00pages
10047-61issue
28eissn
0006-2960issn
1520-4995pii
bi980003cjournal_volume
37pub_type
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