Translational Regulation of RPA2 via Internal Ribosomal Entry Site and by eIF3a.

Translational regulation of RPA2 via internal ribosomal entry site and by eIF3a.

Filed under: Drug and Alcohol Rehabilitation

Carcinogenesis. 2013 Feb 7;
Yin JY, Dong ZZ, Liu RY, Chen J, Liu ZQ, Zhang JT

RPA2 is a subunit of a trimeric RPA complex important for DNA repair and replication. Although it is known that RPA activity is regulated by post-translational modification, whether RPA expression is regulated and the mechanism therein is currently unknown. eIF3a, the largest subunit of eIF3, is an important player in translational control and has been suggested to regulate translation of a subset of mRNAs important for tumorigenesis, metastasis, cell cycle progression, drug response, and DNA repair. In the present study, we show that RPA2 expression is regulated at translational level via internal ribosome entry site (IRES)-mediated initiation in response to DNA damage. We also found that eIF3a suppresses RPA2 synthesis and inhibits its cellular IRES activity by directly binding to the IRES element of RPA2 located at -50 to -150 bases upstream of the translation start site. Taken together, we conclude that RPA2 expression is translationally regulated via IRES and by eIF3a and that this regulation is partly accountable for cellular response to DNA damage and survival.
HubMed – drug

Pharmacokinetic Interactions Between Monoamine Oxidase a Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2013 Feb 7;
Jiang XL, Shen HW, Mager DE, Yu AM

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name “5-MEO”) is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of cytochrome P450 2D6 (CYP2D6) that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5 and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.
HubMed – drug

Quantitative Prediction of Repaglinide-Rifampicin Complex Drug Interactions Using Dynamic and Static Mechanistic Models: Delineating Differential CYP3A4 Induction and OATP1B1 Inhibition Potential of Rifampicin.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2013 Feb 7;
Varma MV, Lin J, Bi YA, Rotter CJ, Fahmi OA, Lam J, El-Kattan AF, Goosen TC, Lai Y

Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate to hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study is to predict the “dosing-time” dependent pharmacokinetic interactions of repaglinide with rifampicin, using mechanistic models. In vitro hepatic transport of repaglinide, characterized using sandwich-cultured human hepatocytes, and intrinsic metabolic parameters were used to build a dynamic whole-body physiologically-based pharmacokinetic (PBPK) model. The PBPK model adequately described repaglinide plasma concentration-time profiles; and successfully predicted area under the plasma concentration-time curve ratios of repaglinide (within ±25% error), dosed (staggered 0-24h) after rifampicin treatment, when primarily considering induction of CYP3A4 and reversible inhibition of OATP1B1 by rifampicin. Further, a static mechanistic “extended net-effect” model incorporating transport and metabolic disposition parameters of repaglinide and interaction potency of rifampicin was devised. Predictions based on the static model are similar to that observed in the clinic (average error ~19%), as well as similar to the PBPK model predictions. Both the models suggested that the combined effect of increased gut extraction and decreased hepatic uptake caused minimal repaglinide systemic exposure change when repaglinide is dosed simultaneously or 1h after the rifampicin dose. On the other hand, isolated induction effect as a result of temporal separation of the two drugs translated to ~5-fold reduction in repaglinide systemic exposure. In conclusion, both dynamic and static mechanistic models are instrumental in delineating the quantitative contribution of transport and metabolism in the dosing-time dependent repaglinide-rifampicin interactions.
HubMed – drug

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