Abstract
Chronic renal failure (CRF) impedes renal excretion of drugs, and their metabolism by reducing the expression of liver cytochrome P450 (CYP450). Uremic serum contains factors, such as parathyroid hormone (PTH), that decrease liver CYP450s. CYP450s are also involved in the metabolism of xenobiotics in the brain. This study investigates (1) the effects of CRF on rat brain CYP450, (2) the role of PTH in the downregulation of brain CYP450s in CRF rats, and (3) the effects of PTH on CYP450s in astrocytes. Protein and mRNA expression of CYP450s were assessed in the brain of CRF and control rats as well as from control or CRF rats that underwent parathyroidectomy (PTX) one week prior to nephrectomy. CYP3A activity was measured using 3-[(3,4-difluorobenzyl) oxy]-5, 5-dimethyl-4-[4-methylsulfonyl) phenyl] furan-2(5H)-one metabolism in brain microsomal preparation. CYP3A protein expression was assessed in primary cultured astrocytes incubated with serum obtained from CRF or control rats, or with PTH. Significant downregulations (≥40%) of CYP1A, CYP2C11 and CYP3A proteins were observed in microsomes from CRF rat brains. CYP3A activity reduction was also observed. CYP3A expression and activity were unaffected in PTX pre-treated CRF rats. Serum of PTX treated CRF rats had no impact on CYP3A levels in astrocytes compared to that of untreated CRF rats. Finally, PTH addition to normal calf serum induced a reduction in CYP3A protein similar to CRF serum suggesting that CRF induced hyperparathyroidism is associated with a significant decrease in CYP450 drug-metabolizing enzymes in the brain, which may have implications in drug response.
- The American Society for Pharmacology and Experimental Therapeutics