Abstract
Uremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6β-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/β, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/β/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes.Uremic toxin accumulation can alter hepatic drug metabolism. Advanced oxidation protein products significantly decrease the expression and activity of CYP1A2 and CYP3A4 via direct activation of the NF-κB pathway. Induction of nuclear translocation of NF-κB inhibits the transcription and translation of CYP1A2 and CYP3A4. The inflammatory cytokines IL-6 and/or TNF-α may mediate this process.
Highlights
Patients with chronic kidney disease (CKD) require a mean of 14.2 concurrent drugs to manage their complications and associated comorbidities, and overdose or underdose errors account for 20.4% of all medical problems in these patients [1]
Treatment with advanced oxidation protein products (AOPPs) reduced cytochromes P450 1A2 (CYP1A2) protein levels in the intestine, kidney, and liver by 44%, 28%, and 35%; CYP3A4 protein levels in the intestine, kidney, and liver were reduced by 46%, 42%, and 40%, respectively (Fig. 2A)
After treatment with AOPPs, the Vmax values for acetaminophen in the sham and 5/6 nx groups were reduced by 57% and 49% and the Km values were reduced by 52% and 64%, respectively
Summary
Patients with chronic kidney disease (CKD) require a mean of 14.2 concurrent drugs to manage their complications and associated comorbidities, and overdose or underdose errors account for 20.4% of all medical problems in these patients [1]. Drug pharmacokinetics are the result of the coordinated action of These authors contributed : Tianrong Xun, Zhufen Lin. CYP3A4 is the main CYP3A family member and is responsible for the metabolism of ~50% of clinically used drugs. CYP3A4 is the main CYP3A family member and is responsible for the metabolism of ~50% of clinically used drugs Many of these drugs are used to treat CKD or its comorbidities [7, 8]. Studies on uremic serum collected from patients with end-stage renal disease (ESRD) have indicated that ESRD decreases the protein expression and activities of the major xenobiotic-metabolizing CYP1A and CYP3A families in rat hepatocytes [9, 10]. The activities of CYP1A2 and CYP3A4 are decreased in CKD and are expected to have significant clinical implications, with altered drug pharmacokinetics and increased adverse drug events in patients with CKD.
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