The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients

Abstract

The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.

Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits

“…Furthermore, rs35107470 was shown the be associated with metabolism of caffeine, which is a CYP1A2 substrate 21 . In line with our recent study, we did not observe other genetic variants that are in linkage disequilibrium with the NFIB‐C variant 31 …”

“… 21 In line with our recent study, we did not observe other genetic variants that are in linkage disequilibrium with the NFIB‐C variant. 31 …”

“…The key enzymes mediating clozapine N ‐demethylation are CYP1A2 and CYP3A4 17 . Just recently, we reported that NFIB is involved in the regulation of several ADME genes, including CYP1A but not CYP3A4 31 . Moreover, nuclear factor I (probably related to NFIB) has been shown to play a role in regulating CYP1A expression by mediating aryl hydrocarbon receptor induction cascade in response to oxidative stress 32 .…”

Drug metabolism and drug transport of the 100 most prescribed oral drugs

“…The same study showed that NFIB rs28379954 T>C carriers that were also CYP2D6 extensive metabolizers had comparable CYP2D6 activity to ultrarapid metabolizers. This highlights that NFIB polymorphisms are important to consider in CYP2D6 drug metabolism 31 …”

“…CPIC guideline recommends alternative analgesics to the two prodrugs, codeine (number 7) and tramadol (number 21), in poor metabolizers or ultrarapid metabolizers, 29 as they are more likely to experience poor pain relief or more adverse effects compared to intermediate metabolizers and extensive metabolizers 30 . The nuclear factor 1B (NFIB) was recently discovered to regulate CYP2D6 gene expression in vitro 31 . The same study showed that NFIB rs28379954 T>C carriers that were also CYP2D6 extensive metabolizers had comparable CYP2D6 activity to ultrarapid metabolizers.…”