1. Determination of benchmark doses for linear furanocoumarin consumption associated with inhibition of cytochrome P450 1A2 isoenzyme activity in healthy human adults
- Author
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Sabine Matou-Nasri and Zeyad Alehaideb
- Subjects
BMD, benchmark dose ,Traditional herbal medicines ,UCL, untreated clearance ,Health, Toxicology and Mutagenesis ,DMSO, dimethyl sulfoxide ,Pharmacology ,Toxicology ,NADPH, β-nicotinamide adenine dinucleotide phosphate hydrogen ,chemistry.chemical_compound ,Furanocoumarin ,5-MOP, 5-methoxypsoralen ,RA1190-1270 ,WM, whole-mixture model ,RPF, relative potency factor ,AIC, Akaike’s information criterion ,THM, traditional herbal medicine ,biology ,Chemistry ,HLM, human liver microsomes ,POD, point-of-departure ,Regular Article ,IC50, concentration at 50 % inhibition ,CA, concentration-addition model ,CYP, cytochrome P450 ,TCL, treated clearance ,NOAEL, no-observed-adverse-effect level ,Isopimpinellin ,USEPA, United States Environmental Protection Agency ,Equivalent ,In vivo ,BMDU, BMD upper bound ,Caffeine ,Cytochrome 1A2 enzyme ,Benchmark dose ,BMR, benchmark response ,LOAEL, lowest-observed-adverse-effect level ,Carcinogen ,ComputingMethodologies_COMPUTERGRAPHICS ,ISOP, isopimpinellin ,CYP1A2 ,Cytochrome P450 ,Metabolism ,HPLC, high-performance liquid chromatography ,Toxicology. Poisons ,BMDL, BMD lower bound ,biology.protein ,log10, common log ,8-MOP, 8-methoxypsoralen ,SD, standard deviation ,Drug metabolism ,BMDS, BMD software - Abstract
Graphical abstract, Highlights • Furanocoumarins are the main CYP1A2 inhibitors in A. majus and A. archangelica. • The inhibitory potencies appear additive to CYP1A2 activity in vitro. • BMD determination for human furanocoumarin-consumption and CYP1A2 inhibition., Millions of individuals globally consume traditional herbal medicines (THMs), which contain abundant amounts of linear furanocoumarins. Linear furanocoumarins (i.e., 8-methoxypsoralen, 5-methoxypsoralen, and isopimpinellin) are inhibitors of cytochrome P450 (CYP) isoenzymes including 1A2, a major enzyme involved in drug metabolism and carcinogen bioactivation. Despite the high consumption of furanocoumarin-containing THMs, no studies have measured the furanocoumarin consumption level that triggers an inhibition to CYP1A2 activity in humans. The first objective was to verify if the potencies of the three furanocoumarins are additive towards the inhibition of CYP1A2 activity in vitro using concentration-addition and whole-mixture chemical-mixture-assessment models. A second objective was to determine the benchmark dose (BMD) with the mixtures of furanocoumarin oral doses, expressed as 8-MOP equivalents, and to assess the in vivo CYP1A2 activity, expressed as inhibition percentages. The in vitro results indicated that the three furanocoumarin inhibitory potencies were additive in the THM extracts, validating the use of the concentration-addition model in total furanocoumarin dose-equivalent calculations. Using the USEPA BMD software, the BMD was 18.9 μg 8-MOP equivalent/kg body weight. This information is crucial for furanocoumarin-related health-assessment studies and the regulation of THMs. Further studies should be performed for the remaining major metabolic enzymes to complete the safety profile of furanocoumarin-containing THMs and to provide accurate warning labelling.
- Published
- 2021