Metabolic and redox barriers in the skin exposed to drugs and xenobiotics

Introduction: Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised.

Areas covered: Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo)

Expert opinion: Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.     

Xenobiotic metabolism gene expression in the EpiDerm™ in vitro 3D human epidermis model compared to human skin

There is an urgent need to validate in vitro human skin models for use in safety testing. An important component of validation is characterizing the metabolizing capacity of these models. We report comparison of the expression of 139 genes encoding xenobiotic metabolizing enzymes in the EpiDerm™ model and human skin. In microarray analysis, the expression of 87% of the genes was consistent between the EpiDerm™ model and human skin indicating the presence of similar metabolic pathways suggesting commonality in function. Analysis of EpiDerm™ models constructed from four donors showed highly comparable expression of xenobiotic metabolizing genes demonstrating reproducibility of the model. Overall, the expression of Phase II enzymes appeared to be more pronounced in human skin and the EpiDerm™ model than that of Phase I enzymes, consistent with the role of skin in detoxification of xenobiotics. Though the basal expression of CYPs in particular was low in EpiDerm™, significant induction of CYP1A1/1B1 activity was observed following treatment with 3-methylcholanthrene. These results indicate that the xenobiotic metabolizing capacity of the EpiDerm™ model appears to be representative of human skin. Models such as EpiDerm™ provide a valuable in vitro approach for evaluation of metabolism and toxicity of cutaneous exposures to xenobiotics.     

The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms

In recent years, public and scientific interest in plant flavonoids has tremendously increased due to postulated health benefits. Whereas the amount of flavonoids ingested with the regular diet is rather low, the use of supplements enriched with these polyphenolics is becoming increasingly popular. This raises concerns about possible interactions of flavonoids with therapeutic drugs, because both are xenobiotics and, thus, share at least partially the same metabolic pathways. A number of in vitro studies have shown effects of flavonoids on enzymes involved in xenobiotic metabolism, like cytochrome P450 monooxygenases and phase II conjugation enzymes, or on membrane transporters involved in drug excretion. Several investigations have also reported changes of drug bioavailability by certain flavonoids. This article attempts to present an overview of flavonoid effects on pathways involved in drug metabolism. It focuses on phase I and phase II enzymes as well as on transporters involved in drug metabolism which are expressed in the gastrointestinal tract.     

New insights on the xenobiotic-sensing nuclear receptors in liver diseases--CAR and PXR--

The xenobiotic receptors CAR and PXR constitute two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. They regulate numerous genes which are involved in drug and xenobiotic metabolism, including Phase I (cytochrome P450), Phase II (conjugation catalyzed by sulfotransferases, glucuronosyltransferases and glutathione S-transferases), and transporters (multidrug resistance proteins, multidrug resistance-associated proteins, and organic anion-transporting polypeptides). Although CAR and PXR were initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on physiological or pathological functions. Recent studies have shown that the activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation. Therefore, in addition to regulating drug elimination pathways, they also play important roles in regulating metabolic pathways. As a result, these receptors may be closely associated with the pathogenesis of many diseases. However, the pathophysiological roles of CAR and PXR are not fully understood. The purpose of this review is to discuss the physiological and pathological roles of CAR and PXR in liver diseases.     

Multidrug and toxic compound extrusion (MATE)-type proteins as anchor transporters for the excretion of metabolic waste products and xenobiotics

1. Multidrug and toxic compound extrusion (MATE)-type transporters, which were first identified as a bacterial drug transporter family, are present in almost all prokaryotes and eukaryotes, and are thus one of the mostly conserved transporter families in nature. 2. Recently, a mammalian MATE transporter was shown to be a long hypothesized electroneutral H(+)/organic cation exporter that is responsible for the excretion of metabolic waste products and xenobiotics at renal brush border membranes and bile canaliculi. Plant MATE-type transporters are involved in the detoxification of metals and secondary metabolites such as phenols through their vesicular storage or extrusion at the plasma membrane. 3. Thus, MATE transporters are involved in one of the basic mechanisms that maintain homeostasis through the excretion of metabolic waste products and xenobiotics in nature.     

Multidrug and toxic compound extrusion (MATE)-type proteins as anchor transporters for the excretion of metabolic waste products and xenobiotics

1.?Multidrug and toxic compound extrusion (MATE)-type transporters, which were first identified as a bacterial drug transporter family, are present in almost all prokaryotes and eukaryotes, and are thus one of the mostly conserved transporter families in nature.

2.?Recently, a mammalian MATE transporter was shown to be a long hypothesized electroneutral H⁺/organic cation exporter that is responsible for the excretion of metabolic waste products and xenobiotics at renal brush border membranes and bile canaliculi. Plant MATE-type transporters are involved in the detoxification of metals and secondary metabolites such as phenols through their vesicular storage or extrusion at the plasma membrane.

3.?Thus, MATE transporters are involved in one of the basic mechanisms that maintain homeostasis through the excretion of metabolic waste products and xenobiotics in nature.     

炎症反应过程中药物转运体调控的研究进展

炎症状态下机体对药物的处置过程会发生显著改变,众多药物代谢酶及转运体的表达和功能发生下调。研究表明机体在该状态下会释放一系列炎症细胞因子对药物代谢酶的表达和功能产生调控,而近年来的研究表明在炎症状态下药物转运体也受到这些细胞因子的调控,且部分转运体的调控呈现明显的种属差异性。进一步的机制研究表明,一些转录因子在调控的信号通路中发挥了重要的作用。本文对炎症状态下药物转运体的调控研究进展进行综述。     

Effects of tryptophan photoproducts in the circadian timing system: searching for a physiological role for aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AhR) mediates adverse effects of dioxins, but its physiological role remains ambiguous. The similarity between AhR and canonical circadian clock genes suggests potential involvement of AhR in regulation of circadian timing. Photoproducts of tryptophan (TRP), including 6-formylindolo[3,2-b]carbazole (FICZ), have high affinity for AhR and are postulated as endogenous ligands. Although TRP photoproducts activate AhR signaling in vitro, their effects in vivo have not been investigated in mammals. Because TRP photoproducts may act as transducers of light, we examined their effects on the circadian clock. Intraperitoneal injection of TRP photoproducts or FICZ to C57BL/6J mice dose dependently induced AhR downstream targets, cytochrome P4501A1 (CYP1A1) and cytochrome P4501B1 mRNA expression, in liver. c-fos mRNA, a commonly used marker for light responses, was also induced with FICZ, and all responses were AhR dependent. A rat-immortalized suprachiasmatic nucleus (SCN) cell line, SCN 2.2, was used to examine the direct effect of TRP photoproducts on the molecular clock. Both TRP photoproducts and FICZ-increased CYP1A1 expression and prolonged FICZ incubation altered the circadian expression of clock genes (Per1, Cry1, and Cry2) in SCN 2.2 cells. Furthermore, FICZ inhibited glutamate-induced phase shifting of the mouse SCN electrical activity rhythm. Circadian light entrainment is critical for adjustment of the endogenous rhythm to environmental light cycle. Our results reveal a potential for TRP photoproducts to modulate light-dependent regulation of circadian rhythm through triggering of AhR signaling. This may lead to further understanding of toxicity of dioxins and the role of AhR in circadian rhythmicity.     

Recent Advances in Carrier-mediated Hepatic Uptake and Biliary Excretion of Xenobiotics

Purpose. Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated transport contributes to hepatic uptake and/ or biliary excretion. In particular, primary active transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as Phase III (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. Methods. The transporters, which have been called P-glycoprotein (MDR), multidrug resistance related protein (MRP) and GS-X pump and which are believed to be involved in the primary active pumping of xenobiotics from the cells, are now known as the ATP-binding cassette (ABC) transporters. In this review, we first describe the HMG-CoA reductase inhibitor, pravastatin, as a typical case of a carrier-mediated active transport system that contributes to the liver-specific distribution in the body. Results. Regarding biliary excretion, we have summarized recent results suggesting the possible contribution of the ABC transporters to the biliary excretion of xenobiotics. We also focus on the multiplicities in both hepatic uptake and biliary excretion mechanisms. Analyzing these multiplicities in transport is necessary not only from a biochemical point of view, but also for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. Conclusions. Clarification of these transport mechanism may provide important information for studying the pharmacokinetics of new therapeutic drugs and furthermore, leads to the development of the drug delivery systems.