Background: The nonrenal clearance of drugs mediated by hepatic reduction is selectively
altered by kidney disease. This study evaluated the influence of uremic serum on the expression and
activity of reductase enzymes.
Methods: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected
from patients with hemodialysis (pre- and post-dialysis session) or control subjects. The mRNA
expression of various aldo-keto (AKR1C) and carbonyl (CBR) reductases were measured. Reductase
metabolic activity was assessed in human liver cytosol or HepG2 cells using naltrexone as a substrate.
Results: Incubation of cells with pre-dialysis serum resulted in significant upregulation of AKR1C4
(by 63.2%) and CBR1 (by 34.6%) versus control serum. This increase was not observed for AKR1C1
and CBR1 with serum collected post-dialysis. While uremic serum had no effect on reductase activity,
some instances with differences in metabolite formation among individual’s pre- and post-dialysis
samples were observed.
Conclusion: Although uremic serum can upregulate mRNA expression of several reductases, this effect
was not observed at the activity level. Future studies are necessary to improve our understanding
of the mechanistic effects of impaired kidney function on drug reduction.