title: Hemodialysis acutely improves hepatic CYP3A4 metabolic activity.
abstract: The uremic syndrome remains poorly understood despite the widespread availability of dialysis for almost four decades. To date, assessment of the biologic activity of uremic toxins has focused primarily on in vitro effects, rather than on specific biochemical pathways or enzymatic activity in vivo. The activity of cytochrome P450 (CYP) 3A4, the most important enzyme in human drug metabolism, is decreased in uremia. The purpose of this study was to assess the effect of hemodialysis and hence varying concentrations of uremic toxins on CYP3A4 activity using the 14C-erythromycin breath test and the traditional phenotypic trait measure, 20-min 14CO2 flux. CYP3A4 activity increased by 27% postdialysis (P = 0.002 compared with predialysis) and was significantly inversely related to plasma blood urea nitrogen concentration (rs= -0.50, P = 0.012), but not to several middle molecules. This is the first study in humans characterizing uremia as a state in which hepatic CYP3A4 activity is acutely improved by hemodialysis.
authors.affiliation: Division of Nephrology and Transplantation, Department of Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
authors.forename: Kofi
authors.initials: K
authors.lastname: Appiah
authors.forename: Scott A
authors.initials: SA
authors.lastname: Kendrick
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Ellen
authors.initials: E
authors.lastname: McMonagle
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
mesh_terms: D000328:Adult; D001806:Blood Urea Nitrogen; D001944:Breath Tests; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D006435:Renal Dialysis; D014118:Toxins, Biological / Q000097:blood; D014511:Uremia / Q000378:metabolism* / Q000628:therapy
chemical_list: D014118:Toxins, Biological; C026865:uremia middle molecule toxins; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human