Current Drug Metabolism (v.14, #6)

Nanoparticle- and Liposome-carried Drugs: New Strategies for Active Targeting and Drug Delivery Across Blood-brain Barrier by Martha Leonor Pinzon-Daza, Ivana Campia, Joanna Kopecka, Ruth Garzon, Dario Ghigo, Chiara Rigant (625-640).
The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) andthe circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundanceof tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugsback into the bloodstream. Nanoparticle- and liposome-carried drugs, because of their increased cellular uptake and reduced effluxthrough ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB.This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for usingnanoparticle- and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle-and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections andepilepsy.

Trichothecenes: Structure-Toxic Activity Relationships by Qinghua Wu, Vlastimil Dohnal, Kami Kuca, Zonghui Yuan (641-660).
Trichothecenes comprise a large family of structurally related toxins mainly produced by fungi belonging to the genusFusarium. Among trichothecenes, type A and type B are of the most concern due to their broad and highly toxic nature. In order to addressstructure-activity relationships (SAR) of trichothecenes, relationships between structural features and biological effects of trichothecenemycotoxins in mammalian systems are summarized in this paper. The double bond between C-9-C-10 and the 12,13-epoxide ringare essential structural features for trichothecene toxicity. Removal of these groups results in a complete loss of toxicity. A hydroxylgroup at C-3 enhances trichothecene toxicity, while this activity decreases gradually when C-3 is substituted with either hydrogen or anacetoxy group. The presence of a hydroxyl group at C-4 promotes slightly lower toxicity than an acetoxy group at the same position. Thetoxicity for type B trichothecenes decreases if the substituent at C-4 is changed from acetoxy to hydroxyl or hydrogen at C-4 position.The presence of hydroxyl and hydrogen groups on C-15 decreases the trichothecene toxicity in comparison with an acetoxy group attachedto this carbon. Trichothecenes toxicity increases when a macrocyclic ring exists between the C-4 and C-15. At C-8 position, anoxygenated substitution at C-8 is essential for trichothecene toxicity, indicating a decrease in the toxicity if substituent change fromisovaleryloxy through hydrogen to the hydroxyl group. The presence of a second epoxy ring at C-7-C-8 reduces the toxicity, whereas epoxidationat C-9-C-10 of some macrocyclic trichothecenes increases the activity. Conjugated trichothecenes could release their toxic precursorsafter hydrolysis in animals, and present an additional potential risk. The SAR study of trichothecenes should provide some crucialinformation for a better understanding of trichothecene chemical and biological properties in food contamination.

Polymer-Based Cancer Nanotheranostics: Retrospectives of Multi-Functionalities and Pharmacokinetics by Ning Han, Yi Yan Yang, Shu Wang, Shusen Zheng, Weimin Fan (661-674).
The pressing need for targeting, detecting, monitoring, and treating diseased cells concomitantly gives rise to multi-functionalnanomedicines, especially those that can combine diagnostic and therapeutic abilities, which are referred to as nanotheranostics. Recently,nanotheranostics are of significant clinical interest as these nanomedicines offer new opportunities to directly visualize drug bloodcirculation and biodistribution, thus facilitating the development of more personalized treatment regimens. To date, much research hasshown the exciting potential of nanotheranostics in cancer therapy and imaging. In particular, the advancements of polymeric nanomaterialsin the past decades have paved the way for the development of cancer nanotheranostics that are primarily comprised of polymers orconjugates of polymer and other types of nanomaterials such as gold nanoparticles, quantum dots, carbon nanotubes, and magnetic ironoxide nanoparticles. Additionally, to improve the therapeutic and diagnostic efficiency of cancer nanotheranostics, various strategies havebeen utilized to provide targeted-delivery across biological barriers and environmental-responsive delivery, leading to the alteration ofpharmacokinetics such as drug distribution, cellular partition, and elimination routes. In this review, we will summarize recent developmentof polymer-based cancer nanotheranostics and some novel strategies to improve their pharmacokinetics, especially biodistribution,followed by a brief discussion of their applications in cancer therapies as well as their toxicity and safety.

Prodrug Design Targeting Intestinal PepT1 for Improved Oral Absorption: Design and Performance by Youxi Zhang, Jin Sun, Yongbing Sun, Yongjun Wang, Zhonggui He (675-687).
Oligopeptide transporter 1 (PepT1) plays an essential role in the oral absorption of di-and tripeptides from the digestion of ingestedprotein. PepT1 has become a striking prodrug-designing target recently, since some poorly absorbed drugs can be modified aspeptidomimetic prodrugs targeting intestinal PepT1 to improve membrane permeability, and eventually oral absorption of the parentdrug. However, little and no comprehensive attempts have been made to especially focus on the recent developments of prodrugs targetingintestinal PepT1. This article summarized biology, transport mechanism, structure-transport requirements for PepT1 and significantadvances on the PepT1-targeted prodrugs within the two decades. The article also aimed to highlight some inspirations and knowledge onthe multifunctional PepT1-targeted design, which are necessary for obtaining optimal prodrug candidates. That is the requirements ofmultifunctional rational PepT1 prodrugs include enough binding affinity for PepT1, controlled or targeted release of parent drug, escapementfrom P-gp mediated efflux and enhanced chemical/metabolic stability. Several types of peptidomimetic prodrugs reported recentlywere discussed in detail in this review.

Cancer chemopreventive activities of various phytochemicals have been attributed to the modulation of xenobiotic disposition,which includes absorption, distribution, metabolism, and excretion. The interaction between xenobiotics and xenobiotic-metabolizing enzymes(XMEs) is bidirectional. XMEs are responsible for the biotransformation of xenobiotics such as bioactivation and detoxification.Conversely, xenobiotics affect XMEs through transcriptional regulation (induction or suppression) and post-translational interactions (inhibitionor activation). Similar relationships also exist between xenobiotics and their transporters. Studies conducted over the past decadehave demonstrated that the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), plays a critical role in the regulation ofdetoxifying enzymes and transporters through a signaling system that senses and responds to redox imbalance. The role of Nrf2 in the interactionbetween chemopreventive phytochemicals and detoxifying enzymes/transporters has become an important topic in cancer chemoprevention.In this review, the genetic and epigenetic factors that contribute to Nrf2-mediated regulation of detoxifying XMEs andtransporters are discussed in the context of cancer chemoprevention. Phytochemicals may modulate the genome as well as epigenome, alteringthe regulation of XMEs and transporters, which may be critical for both cancer chemoprevention and the prevention of other oxidativestress- and inflammatory-related diseases, including cardiovascular, metabolic and neurological pathologies. The pharmacogenomicexpression of XMEs and transporters, with an emphasis on both genomics and epigenetics, will also be discussed.

Enzymes Metabolizing Aristolochic Acid and their Contribution to the Development of Aristolochic Acid Nephropathy and Urothelial Cancer by Marie Stiborova, Vaclav Martínek, Eva Frei, Volker M. Arlt, Heinz H. Schmeiser (695-705).
Aristolochic acid (AA), a plant nephrotoxin and carcinogen, causes aristolochic acid nephropathy (AAN) and its associatedurothelial malignancy, and is hypothesized to be responsible for Balkan endemic nephropathy (BEN). The major component of AA, aristolochicacid I (AAI), is the predominant compound responsible for these diseases. The reductive activation of AAI leads to the formationof covalent DNA adducts. The most abundant DNA adduct, 7-(deoxyadenosin-N6-yl)aristolactam I, causes characteristic AT→TA transversionsfound in the TP53 tumor suppressor gene in tumors from AAN and BEN patients. Understanding which human enzymes are involvedin AAI activation to species forming DNA adducts and/or detoxication to the AAI O-demethylated metabolite, aristolochic acid Ia(AAIa), is important in the assessment of the susceptibility to this carcinogen. This review summarizes the latest data on identifying humanand rodent enzymes participating in AAI metabolism. NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient cytosolic nitroreductaseactivating AAI in vitro and in vivo. In human hepatic microsomes, AAI is activated by cytochrome P450 1A2 (CYP1A2)and, to a lesser extent, by CYP1A1; NADPH:CYP oxidoreductase also plays a minor role. Human and rodent CYP1A1 and 1A2 are alsothe principal enzymes involved in oxidative detoxication of AAI to AAIa in vitro and in vivo. The orientation of AAI in the active sites ofhuman CYP1A1/2 and NQO1 was predicted from molecular modeling and is consistent with the efficient reduction of AAI by them observedexperimentally. Molecular modeling also shows why CYP1A2 plays an important role in the oxidation of AAI to AAIa.

20-Hydroxyeicosatetraenoic Acid is a Potential Therapeutic Target in Cardiovascular Diseases by Osama H. Elshenawy, Anwar Anwar-Mohamed, Ayman O.S. El-Kadi (706-719).
Arachidonic acid (AA) is metabolized by enzymes of the cytochrome P450 (CYP) 4A and CYP4F subfamilies to 20-hydroxyeicosatetraeonic acid (20-HETE), which plays an important role in the cardiovascular system. In the current work, we reviewedthe formation of 20-HETE in different species by different CYPs; 20-HETE metabolism by cyclooxygenases (COXs) and differentisomerases; and the current available inducers and inhibitors of 20-HETE formation in addition to its agonists and antagonists. Moreoverwe reviewed the negative role of 20-HETE in cardiac hypertrophy, cardiotoxicity, diabetic cardiomyopathy, and in ischemia/reperfusion(I/R) injury. Lastly, we reviewed the role of 20-HETE in different hypertension models such as the renin/angiotensin II model, Goldblattmodel, spontaneously hypertensive rat model, androgen-induced model, slat- and deoxycorticosterone acetate (DOCA)-salt-inducedmodels, and high fat diet model. 20-HETE can affect pro- and anti-hypertensive mechanisms dependent upon where, when, and by whichisoform it has been produced. In contrast to hypertension we also reviewed the role of 20-HETE in endotoxin-induced hypotension andthe natriuretic effects of 20-HETE. Based on the recent studies, 20-HETE production and/or action might be a therapeutic target to protectagainst the initiation and progression of cardiovascular diseases.

Selected Pharmaceutical Excipient Prevent Isoniazid and Rifampicin Induced Hepatotoxicity by Tung-Yuan Shih, Shan-Chu Ho, Cheng-Huei Hsiong, Tien-Yu Huang, Oliver Yoa-Pu Hu (720-728).
Background & Aims: The incidence of isoniazid (INH)- and rifampicin (RIF)-induced abnormal liver enzyme activity is 27%but only 19% with INH alone. Cytochrome P450 2E1 (CYP2E1) is thought to contribute to the synergistic effects of RIF and INH. Pharmaceuticalexcipients are inactive ingredients that are added to a pharmaceutical compound. The purpose of this study was to screen excipientsfor CYP2E1 inhibition and identify whether the screened excipients prevented INH/RIF-induced hepatotoxicity.Methods: Fifty-five known pharmaceutical excipients were screened for CYP2E1 inhibition. The hepatotoxic doses of INH and RIF were50 and 100 mg/kg/day, respectively. Hepatotoxicity was assessed by the galactose single point (GSP) method (a US Food and Drug Administration(FDA) recommended quantitative liver function test), liver histopathology, malondialdehyde (MDA) assay, and measurementof aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. We chose the CYP2E1-specific substrate chlorzoxazoneto assess CYP2E1 activity in animal and human.Results: Mannitol inhibited CYP2E1 activity by 54% in mice with INH/RIF-induced hepatotoxicity (p < 0.005). Serum AST, ALT andGSP levels were significantly increased 3.8- to 7.8-fold in these mice (p < 0.005), and these levels could be lowered by mannitol. Mannitolsignificantly alleviated the depletion of hepatic glutathione (GSH) and partially reversed the increase in MDA formation in micetreated with INH/RIF (p < 0.005). Mannitol also decreased CYP2E1 activity by 58% in humans (p < 0.005). Furthermore, an antituberculosis(TB) efficacy assay revealed that mannitol did not affect the anti-TB effects of INH/RIF.Conclusions: Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugsthat induce hepatotoxicity through CYP2E1, such as INH and RIF.