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Biochemical Pharmacology (v.73, #3)

Editorial Advisory Board (pp. iii).

Maternal separation alters drug intake patterns in adulthood in rats by M.C. Moffett; A. Vicentic; Marie Kozel; Paul Plotsky; D.D. Francis; M.J. Kuhar (pp. 321-330).

Maternal separation/handling (MS/H) is an animal model of early life stress that causes profound neurochemical and behavioral alterations in pups that persist into adulthood. Many recent studies have used the MS/H model to study changes in drug effects in adulthood that are linked to behavioral treatments and stressors in the perinatal period. The drug effects focused on in this review are the reinforcing properties of the abused drugs, cocaine and alcohol. A striking finding is that variations in maternal separation and handling cause changes in ethanol and cocaine self-administration. Further, these changes indicate that various manipulations in the perinatal period can have long lasting effects of interest to biochemical pharmacologists. This article will review recent studies on ethanol and cocaine self-administration using the MS/H model and the neurochemical alterations that may play a role in the effects of MS/H on ethanol and cocaine self-administration. Studying the MS/H model can provide important clues into the vulnerability to drug abuse and perhaps identify a crucial window of opportunity for therapeutic intervention.

Keywords: Maternal separation; Cocaine; Ethanol; Drug abuse; Epigenetic mechanisms; Self-administration

Data mining of NCI's anticancer screening database reveals mitochondrial complex I inhibitors cytotoxic to leukemia cell lines by Constance J. Glover; Alfred A. Rabow; Yasemin G. Isgor; Robert H. Shoemaker; David G. Covell (pp. 331-340).

Mitochondria are principal mediators of apoptosis and thus can be considered molecular targets for new chemotherapeutic agents in the treatment of cancer. Inhibitors of mitochondrial complex I of the electron transport chain have been shown to induce apoptosis and exhibit antitumor activity. In an effort to find novel complex I inhibitors which exhibited anticancer activity in the NCI's tumor cell line screen, we examined organized tumor cytotoxicity screening data available as SOM (self-organized maps) (http://www.spheroid.ncifcrf.gov) at the developmental therapeutics program (DTP) of the National Cancer Institute (NCI). Our analysis focused on an SOM cluster comprised of compounds which included a number of known mitochondrial complex I (NADH:CoQ oxidoreductase) inhibitors. From these clusters 10 compounds whose mechanism of action was unknown were tested for inhibition of complex I activity in bovine heart sub-mitochondrial particles (SMP) resulting in the discovery that 5 of the 10 compounds demonstrated significant inhibition with IC₅₀'s in the nM range for three of the five. Examination of screening profiles of the five inhibitors toward the NCI's tumor cell lines revealed that they were cytotoxic to the leukemia subpanel (particularly K562 cells). Oxygen consumption experiments with permeabilized K562 cells revealed that the five most active compounds inhibited complex I activity in these cells in the same rank order and similar potency as determined with bovine heart SMP. Our findings thus fortify the appeal of mitochondrial complex I as a possible anticancer molecular target and provide a data mining strategy for selecting candidate inhibitors for further testing.

Keywords: Abbreviations; NCI; National Cancer Institute; DTP; Developmental Therapeutics Program; SOM; self-organized maps of the Developmental Therapeutics Program of the National Cancer Institute; ETS; mitochondrial electron transport system; MOM; mitochondrial outer membrane; IMS; mitochondrial intermembrane space; ROS; reactive oxygen species; CoQ or “Q”; (Coenzyme Q); CoQ1; (Coenzyme Q1); MPP+; 1-methyl-4-phenylpyridinium ion; bis THF alkane; tetrahydrofuran; SMP; bovine heart sub-mitochondrial particles; BHM; bovine heart mitochondria; DCIP; 2,6-dichlorophenolindophenol; DMSO; dimethyl sulphoxideApoptosis; Mitochondria; NADH: Coenzyme Q oxidoreductase; Enzyme inhibition; Drug discovery; Self-organized maps; K562 leukemia cells

Acylation with diangeloyl groups at C21–22 positions in triterpenoid saponins is essential for cytotoxcity towards tumor cells by Pui-Kwong Chan (pp. 341-350).

Saponins are natural surfactants, found in many plants. Certain saponins are bioactive compounds with anticancer, antivirus and hemolytic activities. The mechanism is unknown. A saponin with antitumor activity was identified in Xanthoceras sorbifolia Bunge ( Sapindaceae) and purified. This saponin is a triterpenoid saponin with a trisaccharide chain attached at C3 of the aglycone and two angeloyl groups acylated at C21 and C22. It inhibits the growth of tumor cells with IC50=2μg/ml in OVCAR3 cells. To study the structure–activity relationship, the diangeloyl group or the carbohydrates of Xanifolia-Y were removed and tested for activity. It was found that removal of both angeloyl groups in C21 and C22 positions completely abolished its activity (IC50>120μg/ml). However, when carbohydrates were remove, its activity was reduced but was not abolished (IC50=10μg/ml). These results suggest that a presence of diangeloyl group in the triterpene structure play an essential role for activity. By comparison, compounds with a similar structure as Xanifolia-Y but have only one angeloyl group at C22: Xanifolia-X (IC50=6μg/ml) or at C21: β-escin (IC50=10μg/ml), have less activity. Results suggest that diangeloyl group in both C21 and C22 positions are important contributing activity. Similar results were observed in hemolytic activity. It is concluded that acylation with angeloyl group at C21 and C22 positions of triterpenoid saponin is essential for its activity.

Keywords: Triterpenoid saponins; Diangeloyl acylation; Anti-tumor; Ovarian cancer; Hemolysis

Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2′-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB by Caroline Smal; Stéphanie Lisart; Marie Maerevoet; Augustin Ferrant; Françoise Bontemps; Eric Van Den Neste (pp. 351-358).

EHEB leukemic cells, which are derived from a patient suffering B-cell chronic lymphocytic leukemia (B-CLL), display intermediate sensitivity to the purine analogue 2-chloro-2′-deoxyadenosine (CdA). Because the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway can rescue cancer cells from apoptotic signals, we investigated MAPK/ERK signaling in EHEB cells in response to CdA. We observed that CdA, at concentrations around its IC₅₀, dose- and time-dependently increased the phosphorylation state of ERK 1/2 (p-ERK), indicating an activation of the MAPK/ERK pathway. This activation required CdA metabolism and de novo protein synthesis, and was independent on caspase activation. Interruption of ERK signaling, using the specific MEK inhibitors U-0126 and PD-98059, significantly enhanced CdA cytotoxicity, evaluated by the MTT assay. Drug interaction analysis showed synergism in the majority of combinations between CdA and MEK inhibitors tested. MEK inhibitors also dramatically increased apoptosis induced by CdA alone, evaluated by caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Collectivelly, these observations show that ERK 1/2 activation elicited by CdA serves as a cytoprotective function and suggest that inhibitors of this pathway could be combined with CdA in the treatment of selected hematological malignancies.

Keywords: MAPK/ERK pathway; 2-Chloro-2′-deoxyadenosine; EHEB; MEK inhibitors; Caspase-3; Chronic lymphocytic leukemia

Inhibition of nitric oxide-guanylate cyclase-dependent and -independent signaling contributes to impairment of β-adrenergic vasorelaxations by cyclosporine by Mahmoud M. El-Mas; Fouad M. Sharabi; Sahar M. El-gowilly; Mahmoud M. Mohy El-Din (pp. 359-367).

This study investigated the role of endothelium- and smooth muscle-dependent mechanisms in the interaction of cyclosporine (CyA), an immunosuppressant drug, with β-adrenoceptor (isoprenaline)-mediated relaxations in isolated rat aortas precontracted with phenylephrine. CyA effects were assessed in the absence and presence of N^G-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor), methylene blue (guanylate cyclase inhibitor), or propranolol (β-adrenoceptor antagonist). In aortas with intact endothelium (E+), pretreatment withl-NAME or methylene blue significantly reduced isoprenaline (1×10⁻⁹ to 1×10⁻⁷M) relaxations in contrast to no effect for tetraethylammonium (K⁺ channel blocker), or diclophenac (cyclooxygenase inhibitor), suggesting a major role for the nitric oxide-guanylate cyclase (NO-GC) pathway, but not endothelial hyperpolarizing factor or vasodilator prostanoids, in isoprenaline responses. Isoprenaline relaxations were still evident, though significantly attenuated, in endothelium-denuded aortas (E−) and were resistant tol-NAME or methylene blue. Acute exposure to CyA (2μM) caused propranolol-sensitive reductions in isoprenaline responses in E+ and E− aortas. The CyA-induced attenuation of isoprenaline responses in E+ aortas largely disappeared inl-NAME-treated aortas and after supplementation withl-arginine, the substrate of nitric oxide. CyA also reduced the endothelium-independent, GC-dependent aortic relaxations evoked by sodium nitroprusside, an effect that was virtually abolished by methylene blue. We conclude that: (i) endothelial and smooth muscle mechanisms contribute to aortic β-adrenoceptor relaxations and both components are negatively influenced by CyA, and (ii) NO-GC signaling plays an integral role in the vascular CyA-β-adrenoceptor interaction. The clinical relevance of the present study is warranted given the established role of impaired vascular function in CyA toxicity.

Keywords: Cyclosporine; Isoprenaline; Nitric oxide; Guanylate cyclase; β-Adrenoceptors; Aorta

Selective cyclooxygenase-2 inhibitors stimulate glucose transport in L6 myotubes in a protein kinase Cδ-dependent manner by Evgenia Alpert; Arie Gruzman; Tamar Tennenbaum; Shlomo Sasson (pp. 368-377).

Selective inhibitors of cyclooxygenase-2 (prostaglandin-endoperoxide synthase-2; COX-2) augment the rate of hexose uptake in myotubes by recruiting glucose transporter-4 (GLUT-4) to the plasma membrane in an insulin- and AMPKα-independent manner [Alpert E, Gruzman A, Lardi-Studler B, Cohen G, Reich R, Sasson S. Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKα-independent manner. Diabetologia 2006;49:562–70]. We aimed at elucidating the molecular interactions that mediate this effect of COX-2 inhibitors in L6 myotubes. The effects of the inhibitors niflumic acid, nimesulide and rofecoxib on activities and phosphorylation state of key proteins in the insulin transduction pathway were determined. These inhibitors did not induce specific tyrosine phosphorylation in IRS-1, could not assemble a functional IRS-PI3K-PKB/Akt complex and did not activate GSK3α/β, JNK1/2, ERK1/2, p38-MAPK or c-Cbl by site-specific phosphorylation(s). Yet, like insulin, they activated mTOR and induced downstream threonine phosphorylation in p70S6K and 4EBP1. However, rapamycin, which inhibits mTOR enzymatic activity, did not interfere with COX-2 inhibitor-induced stimulation of hexose uptake in myotube. Thus, mTOR activation was not required for COX-2 inhibitor-dependent augmentation of hexose transport in myotubes. Because PKCδ has also been shown to activate mTOR, we asked whether COX-2 inhibitors activate mTOR by a prior activation of PKCδ. Indeed, all three inhibitors induced tyrosine phosphorylation in PKCδ and stimulated its kinase activity. Moreover, pharmacological inhibition of PKCδ or the expression of a dominant-negative form of PKCδ in myotubes completely abolished COX-2 inhibitor-dependent stimulation of hexose uptake. This study shows that selective COX-2 inhibitors activate a unique PKCδ-dependent pathway to increase GLUT-4 abundance in the plasma membrane of myotubes and augment the rate of hexose transport.

Keywords: Cyclooxygenase-2 inhibitors; Glucose transport; Niflumic acid; Nimesulide; PKCδ; Rofecoxib; Skeletal muscle

Effects of leptin on apoptosis and adipogenesis in 3T3-L1 adipocytes by Suresh Ambati; Hye-Kyeong Kim; Jeong-Yeh Yang; Ji Lin; Mary Anne Della-Fera; Clifton A. Baile (pp. 378-384).

Leptin has been demonstrated to induce adipose tissue apoptosis, which can contribute to the decrease of adiposity, after either central nervous system or peripheral administration. However, it is not known whether leptin acts only centrally to initiate a signal or can also act directly on adipocytes to induce apoptosis. The objective of this study was to determine the direct effect of leptin on adipocyte apoptosis and adipogenesis in vitro using 3T3-L1 cell lines. An ELISA for single stranded DNA, which is highly specific for apoptotic cells, was used to quantify apoptosis. Preconfluent preadipocytes treated with 10⁻⁹, 10⁻⁸, 10⁻⁷, and 10⁻⁶M leptin showed inhibitory effects on cell viability, and similar observations were also found in maturing preadipocytes treated during day 0–2 and day 2–4 of maturation. After 48h incubation with 10⁻⁶M leptin, LDH release was increased by 24.3% ( p<0.05) in preconfluent preadipocytes and by 108.5% ( p<0.01) in maturing preadipocytes. However, ssDNA analysis revealed no increased apoptosis in preconfluent or maturing preadipocytes or in mature adipocytes treated with leptin. Leptin significantly reduced lipid accumulation and GPDH activity in maturing preadipocytes, demonstrating an inhibitory effect of leptin on adipogenesis. These results indicate that leptin does not act directly to induce adipocyte apoptosis, but can act directly to inhibit maturation of preadipocytes.

Keywords: Leptin; Adipocyte; Apoptosis; Adipogenesis; Viability

Oral administration of phenolic antidiarrheic ingredients prevents ovariectomy-induced bone loss by Nobuaki Moriguchi; Eiichi Hinoi; Takeshi Takarada; Nobuyuki Matsushima; Kyosuke Uno; Yukio Yoneda (pp. 385-393).

In the present study, we have attempted to evaluate the pharmacological actions of three major phenolic antidiarrheic ingredients, including 2-methoxyphenol (2MP), 2-methoxy-4-methylphenol (2M4MP) and 2-methoxy-4-ethyphenol (2M4EP), on the functionality and integrity of bone by in vitro and in vivo experimental techniques. Intermittent oral administration of 2M4MP and 2M4EP, but not 2MP, significantly prevented reductions of bone mineral density in total femur, distal femur and tibia, in addition to alterations of several osteoclastic parameters on histomorphometric analysis, when determined 28 days after ovariectomy in mice. All three phenolic ingredients examined significantly inhibited the developmental increase in the number of multinucleated cells positive to tartrate-resistant acid phosphatase staining in cultured mouse osteoclasts differentiated from bone marrow precursors in the presence of both macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand, which occurred in a concentration-dependent manner at a concentration range of 1μM–1mM without inducing cell death. Moreover, both 2M4MP and 2M4EP at 1mM not only prevented the cell death induced by 0.5mM H₂O₂ in cultured rat calvarial osteoblasts, but also suppressed the generation of intracellular reactive oxygen species in osteoblasts exposed to H₂O₂, with a radical scavenging action as revealed by electron spin resonance analysis. These results suggest that particular phenolic antidiarrheic ingredients may prevent ovariectomy-induced bone loss through a mechanism related to the inhibition of osteoclastogenesis in association with an anti-oxidative property in osteoblasts.

Keywords: Abbreviations; βE2; 17β-estradiol; DCFDA; dihydrodichlorofluorescein diacetate; DMEM; Dulbecco's modified Eagle's medium; DMPO; 5,5-dimethyl-1-pyrroline; N; -oxide; ESR; electron spin resonance; FBS; fetal bovine serum; H; ₂; O; ₂; hydrogen peroxide; LDH; lactate dehydrogenase; MAPK; mitogen-activated protein kinases; M-CSF; macrophage-colony stimulating factor; MEM; minimum essential medium; 2MP; 2-methoxyphenol; 2M4EP; 2-methoxy-4-ethyphenol; 2M4MP; 2-methoxy-4-methylphenol; MNC; multinucleated cell; NF-κB; nuclear factor-κB; PBS; phosphate-buffered saline; PI; propidium iodide; RANKL; receptor activator of nuclear factor-κB ligand; ROS; reactive oxygen species; TRAP; tartrate-resistant acid phosphataseAntidiarrheic; Osteoclasts; Osteoblasts; Ovariectomy; Bone loss

Inhibition of the intestinal absorption of bile acids using cationic derivatives: Mechanism and repercussions by Marta Vicens; Rocio I.R. Macias; Oscar Briz; Alfonso Rodriguez; Mohamad Y. El-Mir; Manuel Medarde; Jose J.G. Marin (pp. 394-404).

To pharmacologically interrupt bile acid enterohepatic circulation, two compounds named BAPA-3 and BAPA-6, with a steroid structure and 1 or 2 positive charges, were obtained by conjugation of N-(3-aminopropyl)-1,3-propanediamine with one or two moieties of glycocholic acid (GC). Both BAPA-3 and BAPA-6 inhibited Na⁺-dependent taurocholate (TC) uptake by Xenopus laevis oocytes expressing rat Asbt, with K_i values of 28 and 16μM, respectively. BAPA-3 reduced V_max without affecting K_m. In contrast, BAPA-6 increased K_m, with no effect on V_max. Uptake of [¹⁴C]-GC by the last 10cm of the rat ileum, perfused in situ over 60min, was inhibited to a similar extent by unlabeled GC, BAPA-3 and BAPA-6. However, the intestinal absorption of these compounds was lower (BAPA-6) or much lower (BAPA-3) than that of GC. When administered orally to mice, both compounds (BAPA-3>BAPA-6) reduced the bile acid pool size, which was accompanied by up-regulation of hepatic Cyp7a1 and Hmgcr and intestinal Ostα/Ostβ. A tendency towards a decreased expression of hepatic Ntcp and an enhanced expression of intestinal Asbt was also observed. Serum biochemical parameters were not affected by treatment with these compounds, except for a moderate increase in serum triglyceride concentrations. In sum, our results suggest that these compounds, in particular BAPA-3, are potentially useful tools for inhibiting the intestinal absorption of bile acids in a non-competitive manner.

Keywords: ASBT; Enterohepatic circulation; Ileum; Intestine; Liver; Polyamine; TransportAbbreviations; ASBT; apical sodium-dependent bile acid transporter; BAPA; bile acid-polyamine derivative; BSEP; bile salt export pump; CDCA; chenodeoxycholic acid; GC; glycocholic acid; NTCP; Na; ⁺; -taurocholate-cotransporting polypeptide; OST; organic solute transporter; TC; taurocholic acid

Irreversible inhibition of glucose-6-phosphate dehydrogenase by the coenzyme A conjugate of ketoprofen: A key to oxidative stress induced by non-steroidal anti-inflammatory drugs? by Carine Asensio; Nicolas Levoin; Cécile Guillaume; Marie-Justine Guerquin; Koukeb Rouguieg; Françoise Chrétien; Yves Chapleur; Patrick Netter; Alain Minn; Françoise Lapicque (pp. 405-416).

Oxidative damage by non-steroidal anti-inflammatory drugs (NSAIDs) has been considered relevant to the occurrence of gastro-intestinal side-effects. In the case of chiral arylpropionate derivatives like ketoprofen (KPF), this mechanism has been evidenced for the R-enantiomer, especially when chiral inversion was observed, and lets us suppose the involvement of CoA conjugates. Glucose-6-phosphate dehydrogenase (G6PD) is the crucial enzyme to regenerate the GSH pool and maintain the intracellular redox potential. This enzyme is known to be down-regulated by palmitoyl-CoA thioester. We hypothesised then that G6PD is the target of carboxylic NSAIDs, via their CoA metabolites. We used molecular docking to localise a putative site in the human G6PD then we chose the Yeast orthologue, as the most suitable species to study experimentally the precise molecular interaction. KPF–CoA was effectively shown to bind covalently to the unique cysteine residue of the yeast enzyme. Binding was found to occur in the same site as palmitoyl-CoA. It was decreased in the presence of an allosteric inhibitor of G6PD, phospho(enol)pyruvate, and was not detected with G6PD of Leuconostoc mesenteroides, which does not possess the allosteric site. This site is distinct from the catalytic site, and probably allosteric, explaining the observed non-competitive inhibition of its activity by KPF–CoA. KPF–CoA was shown to induce the production of reactive oxygen species in Caco-2 cells, where its inhibition of G6PD activity was observed.

Keywords: Abbreviations; COX; cyclooxygenase; DHEA; dehydroepiandrosterone; G6PD; glucose-6-phosphate dehydrogenase; KPF; ketoprofen; NAK; non-acylating analogue of KPF–CoA; NSAID; non-steroidal anti-inflammatory drugs; PEP; phospho(enol)pyruvate monopotassium; ROS; reactive oxygen speciesGlucose-6-phosphate dehydrogenase; Chiral NSAID; Coenzyme A metabolite; Oxidative stress; Digestive side-effects; Allosteric site

Chain length dependence of the interactions of bisquaternary ligands with the Torpedo nicotinic acetylcholine receptor by Chris R.J. Carter; Liren Cao; Hideki Kawai; Peter A. Smith; William F. Dryden; Michael A. Raftery; Susan M.J. Dunn (pp. 417-426).

The interactions of a series of bisholine esters [(CH₃)₃N⁺CH₂CH₂OCO–(CH₂)_n–COOCH₂CH₂N⁺(CH₃)₃] with the Torpedo nicotinic acetylcholine receptor have been investigated. In equilibrium binding studies, [³H]-suberyldicholine ( n=6) binds to an equivalent number of sites as [³H]-acetylcholine and with similar affinity ( K_D∼15nM). In competition studies, all bischoline esters examined displaced both radioligands in an apparently simple competitive manner. Estimated dissociation constants ( K_I) showed clear chain length dependence. Short chain molecules ( n≤2) were of lower affinity ( K_I's of 150–300nM), whereas longer ligands ( n>6) had high affinity similar to suberyldicholine. Functional responses were measured by either rapid flux techniques using Torpedo membrane vesicles or voltage-clamp analyses of recombinant receptors expressed in Xenopus oocytes. Both approaches revealed that suberyldicholine (EC50∼3.4μM) is 14–25-fold more potent than acetylcholine. However, suberyldicholine elicited only about 45% of the maximum response of the natural ligand, i.e., it is a partial agonist. The potency of this bischoline series increased with chain length. Whereas the shorter ligands ( n≤3) displayed potencies similar to acetylcholine, longer ligands ( n≥4) had similar (or higher) potency to suberyldicholine. Ligand efficacy had an approximately bell-shaped dependence on chain length and compounds where n≤3 and ≥8 were very poor partial agonists. Based on estimates of interonium distances, we suggest that bisquaternary ligands can interact with multiple binding sites on the nAChR and, depending on the conformational state of the receptor, these sites are 15–20Å apart.

Keywords: Torpedo; nicotinic acetylcholine receptor; Bisquaternary agonists; Suberyldicholine; Xenopus; oocyte expression; Ligand-gated ion channels

Dicoumarol impairs mitochondrial electron transport and pyrimidine biosynthesis in human myeloid leukemia HL-60 cells by David González-Aragón; Julia Ariza; José M. Villalba (pp. 427-439).

Dicoumarol, a competitive inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), increases intracellular superoxide and affects cell growth of tumor cells. This work was set to establish a mechanistic link between dicoumarol, superoxide and cell cycle alterations in HL-60 cells. Using ES936, a mechanism-based irreversible inhibitor of NQO1, we demonstrate that NQO1 inhibition is not a major factor involved in superoxide boost. Mitochondrial Complexes II, III and IV were directly inhibited by dicoumarol. Succinate, which inhibits superoxide generation by reversed electron flow in Complex II, significantly decreased superoxide boost in dicoumarol-treated cells and in isolated mitochondria incubated with dicoumarol and decylubiquinol. Superoxide generation in cells was strongly potentiated by blocking the quinone site of Complex II with thenoyltrifluoroacetone, supporting the involvement of cytochrome b₅₆₀ to drive electrons for increasing superoxide. Simultaneous inhibition of the mitochondrial chain upstream ubiquinone and displacement of succinate from the Complex II active site is proposed as a major mechanism to explain how dicoumarol increases superoxide in HL-60 cells. Dicoumarol-treated cells accumulated in S phase due to the impairment of pyrimidine biosynthesis at dihydroorotate dehydrogenase step because blockade was overcome by addition of exogenous uridine or orotate, but not by dihydroorotate. We demonstrate for the first time that dicoumarol inhibits mitochondrial electron transport, induces superoxide release by reversed electron flow in Complex II, and inhibits pyrimidines biosynthesis. These actions must be taken into account when considering dicoumarol effects on cells.

Keywords: Abbreviations; CLAP; chymostatin, leupeptin, antipain and pepstatin; ES936; 5-methoxy-1,2-dimethyl-3-[(4-nitrophenol)methyl]-indole-4,7-dione; DB; decylubiquinone; DBH; ₂; decylubiquinol; DCPIP; 2,6-dichlorophenolindophenol; FCS; fetal calf serum; HEt; hydroethidine; NQO1; isoform 1 of the cytosolic NAD(P)H:(quinone acceptor) oxidoreductase, DT-diaphorase; ROS; reactive oxygen species; TTFA; thenoyltrifluoroacetoneCell cycle; Dicoumarol; Mitochondria; NQO1; Pyrimidines biosynthesis; Superoxide

Gene expression and regulation of drug transporters in the intestine and kidney by Tomohiro Terada; Ken-ichi Inui (pp. 440-449).

Intestinal absorption and renal secretion of ionic drugs are controlled by a number of drug transporters expressed at the brush-border and basolateral membranes of epithelial cells. Over the last several years, considerable progress has been made regarding the molecular identification and functional characterization of drug transporters. Under some physiological and pathophysiological conditions, the expression and transport activity of drug transporters are changed, affecting the pharmacokinetics of substrate drugs. The regulation of transport activity in response to endogenous and exogenous signals can occur at various levels such as transcription, mRNA stability, translation, and posttranslational modification. Transcriptional regulation is of particular interest, because changes in transport activity are dynamically regulated by increases or decreases in levels of mRNA expression. The tissue-specific expression of drug transporters is also under transcriptional control, and recent studies using clinical samples from human tissues have revealed the expression profiles of drug transporters in the human body. The purpose of this research updates is to review the recent progress in the study of the gene expression and regulation of intestinal and renal drug transporters.

Keywords: Abbreviations; ABC; ATP-binding cassette; ATF; activating transcription factor; BCRP; breast cancer resistance protein; Cdx2; caudal-related homeobox protein; CRE; cAMP responsive element; CREB; CRE binding protein; EMSA; electrophoretic mobility shift assay; HNF-4α; hepatocyte nuclear factor-4α; MDR; multidrug resistance protein; MRP; multidrug resistance-associated protein; OAT; organic anion transporter; OCT; organic cation transporter; OCTN; novel organic cation transporter; PEPT; peptide transporter; Pgp; P-glycoprotein; PKA; protein kinase A; PPARα; peroxisome proliferator-activated receptor α; SLC; solute carrierDrug transporters; Transcription; PEPT; OAT; OCT

Harnessing the hypoxia-inducible factor in cancer and ischemic disease by M. Christiane Brahimi-Horn; Jacques Pouysségur (pp. 450-457).

The α/β-heterodimeric transcription factor hypoxia-inducible factor (HIF) functions when the oxygen level in tissues is low, i.e. when the tissue microenvironment becomes hypoxic, and is non-functional when the level of oxygen is high. Certain pathophysiological conditions such as ischemic disorders and cancer encounter low levels of local tissue oxygenation due to a defective or insufficient vasculature. Highly proliferating tumour cells rapidly form into a mass that becomes located too far from the vasculature to be nourished and oxygenated. Under such conditions HIF activates or represses a vast array of genes that in particular, initiate the formation of new blood vessels and modify metabolism. In this way the tumour mass re-establishes conditions favourable for further proliferation. Interest is being expressed in the direct repression or stimulation of HIF activity, respectively, in the treatment of cancer and of ischemic disorders. The modulation of other HIF-target genes implicated, in particular, in tumour metabolism and intracellular pH control may also prove to be useful in cancer therapy. However, before going further a better understanding of the basics of the HIF signalling pathway is essential. This review will introduce the reader to the molecular mechanisms that regulate HIF and some of the biological consequences of its action, in particular in tumour metabolism, growth and invasion. Approaches to either enforce tumour regression or increase blood vessel formation through the targeting of HIF or its downstream effectors will also be discussed.

Keywords: Abbreviations; bHLH; basic-helix-loop-helix; BNIP3; Bcl-2/adenovirus EIB 19kDa-interacting protein 3; CITED; CBP/p300 interacting transactivator with ED-rich tail 2; CBP; CREB binding protein; Epo; erythropoietin; FIH; factor inhibiting HIF-1; FH; fumarate hydratase; HIF; hypoxia-inducible factor; HO-1; haem oxygenase; HRE; hypoxia response element; iNO-2; inducible nitric-oxide synthase 2; IRES; internal ribosome entry site; mTOR; mammalian target of rapamycine; NHE1; Na; ⁺; /H; ⁺; exchanger; 2-OG; 2-oxoglutarate; ODDD; oxygen degradation dependent domain; PAS; Per-Arnt-Sim; PGI; phosphoglucose isomerase; PTEN; phosphatase and tensin; PHD; prolyl hydroxylase domain; SDH; succinate dehydrogenase; TAD; transcriptional activation domain; TCA; tricarboxylic acid; VEGF; vascular endothelial growth factor; VHL; von Hippel-LindauAngiogenesis; Arrest-defective protein; Cancer; Factor inhibiting HIF; Hypoxia-inducible factor; Oxygen-sensor; Prolyl hydroxylase domain; Tumour invasion and metabolism

Erratum to “Sodium tanshinone IIA sulfonate derived from Slavia miltiorrhiza Bunge up-regulate the expression of prolactin releasing peptide (PrRP) in the medulla oblongata in ovariectomized rats” [Biochem. Pharmacol. 72 (5) (2006) 582–587] by Yao Xiao; Wang Xiao Qing; Ma Shu Lan; Chen Bo Ying (pp. 458-458).

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Biochemical Pharmacology (v.73, #3)