Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Abstract

The cytochrome P450 belonging to the CYP2B subfamily has long been of great interest because it can be induced by xenobiotics. While a well known diagnostic ligand-receptor theory explains the induction of the CYP1A subfamily, the mechanism by which xenobiotics induce the CYP2B subfamily is not fully understood. Although the constitutive androstane receptor (CAR) undoubtedly plays a crucial role in the induction, many questions regarding the mechanism of CAR activation by xenobiotics have not yet been answered. It is a puzzle that many structurally-unrelated chemicals can increase the expression of the CYP2B subfamily. This may support a mechanism(s) distinct from the signaling induced by ligand-receptor binding. Indeed, phenobarbital, a typical inducer, cannot associate with CAR. Thus, no one is able to answer a fundamental question: what is the initial target of xenobiotics to produce induced expression of CYP2B enzymes? In this review, we survey the research history of CYP2B induction, list the inducers reported so far, and discuss the mechanism of induction including the target site of inducers.

Organochlorines and risk of non‐Hodgkin lymphoma

“…44,45 PCBs can also activate CYP2B enzymes independently of the Ah receptor pathway, and these PCB congeners are sometimes referred to as phenobarbital (PB)-like inducers. [46][47][48] Although not as potent as coplanar PCB congeners, which are rare in the environment, other dioxin-like PCB congeners (nos. 105, 118 and 156) can bind the Ah receptor and activate CYP1A1, have PB-like induction potency and high potential toxicity.…”

Effect of xenobiotics on microrna expression in rat liver

“…В таком случае miR-152 и miR-143 в зависимости от применяемого ксенобиотика могут ингибировать негативный регулятор экспрессии гена CYP2B, в промоторе которого имеется сайт связывания (NE) [21]. Интересно, что выявлена индуктор-специфичная экспрессия именно гена CYP2B, механизм которой остается неизвестным [22]. Возможно, что активация специфичных микроРНК может быть одной из причин различного действия химических соединений на экспрессию CYP2B.…”

Ambient tonicity and intestinal cytochrome CYP3A

“…Because of their crucial role in drug metabolism, CYP enzymes have been foci of intense research in drug discovery and development [3]. There are 57 functional human CYP isoforms and 58 pseudogenes [4], but the 3A subfamily of P450 enzymes constitutes the most abundant CYP enzymes in human adult liver (for a comprehensive review of these enzymes, refer [5][6][7][8][9]). …”