Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters

Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Triptolide, a diterpene triepoxide, is a major active component of extracts derived from the medicinal plant Tripterygium wilfordii Hook F (TWHF). Triptolide has multiple pharmacological activities including anti-inflammatory, immune modulation, antiproliferative and proapoptotic activity. So, triptolide has been widely used to treat inflammatory diseases, autoimmune diseases, organ transplantation and even tumors. Triptolide cannot only induce tumor cell apoptosis directly, but can also enhance apoptosis induced by cytotoxic agents such as TNF-α, TRAIL and chemotherapeutic agents regardless of p53 phenotype by inhibiting NFκB activation. Recently, the cellular targets of triptolide, such as MKP-1, HSP, 5-Lox, RNA polymerase and histone methyl-transferases had been demonstrated. However, the clinical use of triptolide is often limited by its severe toxicity and water-insolubility. New water-soluble triptolide derivatives have been designed and synthesized, such as PG490-88 or F60008, which have been shown to be safe and potent antitumor agent. Importantly, PG490-88 has been approved entry into Phase I clinical trial for treatment of prostate cancer in USA. This review will focus on these breakthrough findings of triptolide and its implications. Copyright © 2011 Elsevier B.V. All rights reserved.

Triptolide (TP), a major active and toxic ingredient isolated from the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF). A widespread application of TP raises the question on the safety of its use in clinical settings. The metabolism of TP is mediated by hepatic cytochrome P450s, and a strong correlation exists between TP toxicity and CPY3A. Toxicity of TP and the molecular mechanisms of its toxic effects have been studied in recent years. Studies have demonstrated that TP exposure results in injury of various organs, including the liver, kidney, testes, ovary, and heart in animals and even in humans, according to clinical case reports. Moreover, on the cellular level, TP has been reported to be associated with diverse toxic effects, encompassing membrane damage, mitochondrial disruption, metabolism dysfunction, endoplasmic reticulum stress, oxidative stress, apoptosis and autophagy. This review presents an overview of the current findings related to TP toxicity with an emphasis on biological targets and the molecular mechanisms that may be involved, thus providing a systematic understanding of the mechanisms by which TP affects cells and tissues in vitro and in vivo.