Interactions of safrole and isosafrole and their metabolites with cytochromes P-450

Inhibition of Cytochrome P450 Enzymes

“…Interestingly, the difference spectrum resulting from these interactions exhibited both type II as well as MI complex spectral features, thereby revealing the simultaneous occurrence of dual P450 binding modes [196] Its inherent MDP activation to a carbene complex is consistent with Examples of MDP compounds naturally present in herbal remedies, oils, and spices documented to be quasi-irreversible inactivators of certain P450 isoforms via MI complexation Note that not only the concentrations of some of these MDP compounds required to inactivate P450s may exceed the levels present naturally, but also may vary widely from batch to batch the concurrent detection of a catechol metabolite [196] Reports of adverse herb-drug interactions upon intentional or accidental coingestion of high enough doses of MDPs naturally present in dietary supplements, ritual beverages, and traditional phytotherapeutic medicines (Fig 55) are also clinically abundant [143-146] Safrole and isosafrole present (Fig 55) in oil of Sassafras, once used as a root-beer flavoring agent, but now banned because of its carcinogenic potential, rank among the first discovered MDPs as P450 inhibitors [197][198][199][200] Isosafrole, a precursor in the chemical manufacture of the fragrance heliotropin (piperonal) and the recreational psychostimulant MDMA, is a mechanism-based substrate/inactivator of CYP1A2 that in rats was found to produce a stable, isolable CYP1A2-MI complex and thus to "induce" CYP1A2 via stabilization [141] Sesame oil also contains several MDPs such as the antioxidant sesamol, and lignans such as the dietary fat-reducing supplement sesamin (Fig 55) and sesamolin [2001] Although CYP2C9 and CYP1A2 metabolized sesamin to its monocatechol metabolite, only CYP2C9 underwent MBI, most likely via an MI complex with apparent K I and k inact values for diclofenac-4ʹ-hydroxylation of 22 μM and 0.13 min − 1 , respectively [201,202] Sesamin was also reported to potently inhibit CYP3A -dependent metabolism of α-and γ-tocopherols to their corresponding 3ʹ-and 5ʹ-δ-carboxychroman metabolites in HepG2 cells [203], although it is unclear whether such inhibition involves an MDP-associated MBI (Fig 55) present at comparable levels in extracts popularly used as a medicinal immunostimulant against common cold and upper respiratory tract infections, were shown to inhibit CYP2C9-dependent diclofenac-4ʹ-hydroxylation, CYP2D6-dependent bufuralol-1ʹ-hydroxylation, and CYP3A4-dependent testosterone 6β-hydroxylation [212] Of the two MDP alkaloids, berberine was the most potent against CYP2D6, exhibiting an IC 50 value of≈ 45 μM, whereas it was the least inhibitory of CYP3A4 (with an IC 50 value of≈ 400 μM). On the other hand, the (+) and (−) hydrastine isomers were only weakly inhibitory towards CYP2D6 (with an IC 50 value of≈ 350 μM for each isomer), but inhibited CYP3A4 with K I values of 25 and 30 μM, respectively [212] An apparent K I value of ≈ 110 μM and a k inact value of 023 ...…”