Role of JNK in the Regulation of Xenobiotic Metabolizing Function of Hepatocytes

Abstract

We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein kinase in the biotransformation of this psychotropic agent by hepatocytes was demonstrated. JNK inhibitor added to the liver homogenate containing antidepressant enhanced and accelerated the formation of the only pharmacologically active venlafaxine metabolite O-desmethylvenlafaxine in the cell suspension. The results show the promise of studying modifiers of activity of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop a fundamentally new approach to control the transformation of xenobiotics and to create a new class of pharmaceutical, target regulators of drugs metabolism.

C-Jun N-Terminal Kinases Inhibition: A New Approach to the Regulation of Venlafaxine Pharmacokinetics

“…However, in this context, it seems reasonable to anticipate an accelerated uptake into tissues under the influence of the JNK inhibitor, not only for VLF (as suggested earlier) but also for O-DVLF. This is because an increase in the intensity of venlafaxine biotransformation into O-DVLF under the influence of a JNK inhibitor [7,12] should logically result in an increased plasma concentration of this metabolite. Moreover, the confirmation of the involvement of this mechanism (rapid tissue penetration of VLF) in the observed patterns could serve as a foundation for developing a fundamentally new approach to enhancing the efficacy of antidepressant therapy with venlafaxine.…”

“…Given the relatively high affinity of both VLF and O-DVLF for nervous tissue [8], this opens up prospects for increasing the concentration of both venlafaxine itself (which possesses independent psychotropic pharmacological activity [13]) and its active metabolite (O-DVLF) [7,17] in the brain. This is particularly significant considering their relatively high affinity for nervous tissue, especially venlafaxine [18].…”

“…However, the specific roles of individual signal transduction pathways in regulating the xenobioticmetabolizing function of cells competent in this regard are largely unknown. Simultaneously, uncovering the involvement and distinct roles of particular signaling molecules in the biotransformation of pharmacologically active substances can form the basis for the development of innovative approaches to personalized pharmacotherapy [7][8][9][10][11]. Therefore, it is pertinent to investigate the potential for controlling the intensity and nature of substance transformation within the body by regulating intracellular signal transduction in metabolizing cells and creating 'Targeted Regulators of Xenobiotic/Drug Metabolism' [7,12].…”

“…It has been demonstrated that JNK plays a role in regulating various functions of different cellular components, and inhibitors targeting this signaling molecule have been identified to possess neuroprotective, anti-inflammatory, hemostimulatory, and several other pharmacological properties [2]. Additionally, the significant role of JNK in regulating the metabolism of the antidepressant venlafaxine by liver cells is welldocumented [7,12].…”

“…We have previously demonstrated the potential for accelerating the conversion of venlafaxine to O-DVLF using a JNK inhibitor in vitro [7,12]. However, the precise nature of the modification of this antidepressant's metabolism with selective JNK blockade in vivo and the resulting alterations in its pharmacokinetics remain unknown.…”