The effects of diet and geographic ancestry on drug-metabolising enzyme activity in Europeans and South Asians

Abstract

Drug metabolism is a major determinant of variability in response to medicines. The effects of genetics and diet on cytochrome P450 (CYP) activity differ between geographic ancestries. This thesis explores how cruciferous vegetable-enriched diets, genetics and CYP activity interact to explain variability in drug response between Europeans and South Asians. A systematic review with meta-analyses was conducted on Cruciferae dietary interventions (Chapter 2). From the 23 studies included into the review, it was found that only CYP1A2 and GST-α were eligible for meta-analysis, and both enzyme activities were increased 15-40% by cruciferous vegetable consumption. Overall data displayed marked heterogeneity. CYP2C19, CYP2C9, CYP2D6 and CYP3A4 were not represented in this literature, nor were any studies designed to compare effects between ancestry groups. Two bioanalytical methods using UHPLC-MS/MS were optimised and validated according to US FDA guidelines (Chapters 3 and 4): a CYP-phenotyping cocktail and a sulforaphane (SUL) assay in human plasma. Both assays met US FDA requirements and were used successfully to analyse samples collected during this project. A clinical study investigated the effects of a broccoli-enriched diet on CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 activities in Europeans and South Asians (Chapter 5). Interactions with CYP and phase II variant genotypes were also explored. CYP1A2 activity increased after 6 days of broccoli consumption in Europeans, but not South Asians. After broccoli consumption, there was evidence of inhibition of CYP2D6 and acute inhibition followed by return to baseline for CYP2C19. CYP2C9 activity was higher in South Asians compared to Europeans. The effects of variant genotypes on each of the enzymes were discussed, as was SUL exposure. Overall, this research contributes to a better understanding of how diet, genetics and ancestry affect variability in drug metabolism.