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Biochemical Pharmacology (v.76, #6)

Editorial Advisory Board (pp. iii).

Uracil in DNA: Consequences for carcinogenesis and chemotherapy by Sondra H. Berger; Douglas L. Pittman; Michael D. Wyatt (pp. 697-706).

The synthesis of thymidylate (TMP) occupies a convergence of two critical metabolic pathways: folate metabolism and pyrimidine biosynthesis. Thymidylate is formed from deoxyuridylate (dUMP) using N⁵, N¹⁰-methylene tetrahydrofolate. The metabolic relationship between dUMP, TMP, and folate has been the subject of cancer research from prevention to chemotherapy. Thymidylate stress is induced by nutritional deficiency of folic acid, defects in folate metabolism, and by antifolate and fluoropyrimidine chemotherapeutics. Both classes of chemotherapeutics remain mainstay treatments against solid tumors. Because of the close relationship between dUMP and TMP, thymidylate stress is associated with increased incorporation of uracil into DNA. Genomic uracil is removed by uracil DNA glycosylases of base excision repair (BER). Unfortunately, BER is apparently problematic during thymidylate stress. Because BER requires a DNA resynthesis step, elevated dUTP causes reintroduction of genomic uracil. BER strand break intermediates are clastogenic if not repaired. Thus, BER during thymidylate stress appears to cause genome instability, yet might also contribute to the mechanism of action for antifolates and fluoropyrimidines. However, the precise roles of BER and its components during thymidylate stress remain unclear. In particular, links between BER and downstream events remain poorly defined, including damage signaling pathways and homologous recombination (HR). Evidence is growing that HR responds to persistent BER strand break intermediates and DNA damage signaling pathways mediate cross talk between BER and HR. Examination of crosstalk among BER, HR, and damage signaling may shed light on decades of investigation and provide insight for development of novel chemopreventive and chemotherapeutic approaches.

Keywords: Abbreviations; TS; thymidylate synthase; TMP; thymidylate; TTP; thymidine triphosphate; dUMP; deoxyuridylate; dUTP; deoxyuridine triphosphate; CH; ₂; H; ₄; PteGlu; N; ⁵; ,; N; ¹⁰; -methylenetetrahydrofolate; 5-FU; 5-fluorouracil; FdUrd; 5-fluoro-2′-deoxyuridine; RTX; raltitrexed (Tomudex); TLS; thymineless stress; TLD; thymineless death; DSB; double strand breaks; MTHFR; methylenetetrahydrofolate reductase; MTHFD; methylenetetrahydrofolate dehydrogenase; TK; thymidine kinase; DHFR; dihydrofolate reductase; dUTPase; deoxyuridine triphosphate nucleotidohydrolase; UDG; uracil DNA glycosylase; BER; base excision repair; PARP; poly (ADP-ribose) polymerase; HR; homologous recombination; SCE; sister chromatid exchangeThymidylate deprivation; Folate deficiency; Base excision repair; Homologous recombination

Interference with actin dynamics is superior to disturbance of microtubule function in the inhibition of human ovarian cancer cell motility by Marcel N.A. Bijman; Maria P.A. van Berkel; Geerten P. van Nieuw Amerongen; Epie Boven (pp. 707-716).

Cellular movement is mainly orchestrated by the actin and microtubule cytoskeleton in which Rho GTPases closely collaborate. We studied whether cytoskeleton-interfering agents at subtoxic and 50% growth-inhibiting concentrations affect motility of five unselected human ovarian cancer cell lines. Cisplatin and doxorubicin as control cytotoxic agents were not effective, the microtubule-targeting agents docetaxel, epothilone B and vinblastine only marginally inhibited cell motility, while the actin-targeting agent cytochalasin D was most potent in hampering both cell migration and invasion. Disturbance of microtubule dynamics by docetaxel did not importantly affect the cellular structures of β-tubulin and F-actin. In contrast, hindrance of actin dynamics by cytochalasin D resulted in loss of lamellipodial extensions, induced thick layers of F-actin and disorder in cellular organization. In OVCAR-3 cells the activity of Rac1 was only slightly diminished by docetaxel, but clearly reduced by cytochalasin D. In conclusion, targeting the actin cytoskeleton might provide a means to prevent metastasis formation.

Keywords: Ovarian cancer; Cytoskeleton; Motility; Microtubule-targeting agents; F-actin

Characterization of Eltenac and novel COX-2 selective thiopheneacetic acid analogues in vitro and in vivo by Thomas Klein; Frank Dullweber; Christoph Brehm; Walter Prinz; Monika Baudler; Volker Figala; Michael Herrmann (pp. 717-725).

We assessed the effect of novel selective thiopheneacetic acids on cyclooxygenase isoenzymes in vitro and in vivo. Thiopheneacetic acid Eltenac and derivatives were investigated in this study. In human whole blood experiments these derivatives were potent inhibitors of COX-2 (IC₅₀=0.02–0.4μM) with less pronounced effect on COX-1 (IC₅₀=0.15–5.6μM). With COX-1/COX-2 ratios between 7.5- and 16-fold they are in the range of Celecoxib (13-fold). The parent drug Eltenac demonstrated no selectivity for COX-2.In a rat paw edema model, these compounds showed reduction of edema volume in the range of 36–45% at 10mg/kg (Eltenac 52%, Diclofenac 51%). However, the compounds were superior to Diclofenac and Eltenac with respect to their ulcerogenic and gastrointestinal properties. Introduction of a nitrate-ester moiety to either Eltenac or a derivative did neither improve selectivity or potency in vitro , nor ulcerogenicity in vivo.Molecular modeling of selective thiopheneacetic acid derivatives to the active site of human COX-2 suggested similar binding properties as Lumiracoxib and Diclofenac.In summary, modification of Eltenac generates moderately selective COX-2 drugs in the range of Celecoxib with respect to potency and selectivity. The drugs showed potent anti-inflammatory properties and significant improvement of animal survival in a sub-chronical experimental set up. Thiopheneacetic derivatives are characterized by low p K_a values, short microsomal half-lives and binding mode to COX-2 similar to Diclofenac and Lumiracoxib. These properties may also have an impact on the transient inhibition of COX-2-dependent prostacyclin, thereby being less associated with vascular complications.

Keywords: Abbreviations; NSAID; non-steroidal anti-inflammatory drug; COX; cyclooxygenase; COXib; COX-2 selective inhibitorNSAID; Cyclooxygenase; COXib; Prostacyclin; Eltenac

The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT) by Barbara L.F. Kaplan; Alison E.B. Springs; Norbert E. Kaminski (pp. 726-737).

Cannabidiol (CBD) is a cannabinoid compound derived from Cannabis Sativa that does not possess high affinity for either the CB1 or CB2 cannabinoid receptors. Similar to other cannabinoids, we demonstrated previously that CBD suppressed interleukin-2 (IL-2) production from phorbol ester plus calcium ionophore (PMA/Io)-activated murine splenocytes. Thus, the focus of the present studies was to further characterize the effect of CBD on immune function. CBD also suppressed IL-2 and interferon-γ (IFN-γ) mRNA expression, proliferation, and cell surface expression of the IL-2 receptor alpha chain, CD25. While all of these observations support the fact that CBD suppresses T cell function, we now demonstrate that CBD suppressed IL-2 and IFN-γ production in purified splenic T cells. CBD also suppressed activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) transcriptional activity, which are critical regulators of IL-2 and IFN-γ. Furthermore, CBD suppressed the T cell-dependent anti-sheep red blood cell immunoglobulin M antibody forming cell (anti-sRBC IgM AFC) response. Finally, using splenocytes derived from CB1^−/−/CB2^−/− mice, it was determined that suppression of IL-2 and IFN-γ and suppression of the in vitro anti-sRBC IgM AFC response occurred independently of both CB1 and CB2. However, the magnitude of the immune response to sRBC was significantly depressed in CB1^−/−/CB2^−/− mice. Taken together, these data suggest that CBD suppresses T cell function and that CB1 and/or CB2 play a critical role in the magnitude of the in vitro anti-sRBC IgM AFC response.

Keywords: Abbreviations; AFC; antibody-forming cell; CBD; cannabidiol; THC; delta-9-tetrahydrocannabinol; IL-2; interleukin-2; IFN-γ; interferon-gammaCannabinoid; Interleukin-2; Interferon-gamma; NFAT; AP-1

α-Galactosylceramide modulates the induction of indoleamine 2,3-dioxygenase in antigen presenting cells by Silvia Fallarini; Tiziana Paoletti; Luigi Panza; Grazia Lombardi (pp. 738-750).

The glycolipid α-galactosylceramide (α-GalCer), when presented on CD1 molecules by antigen presenting cells (APCs) to invariant NKT (iNKT cells), is a potent immunomodulator. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the catabolism ofl-tryptophan along the kynurenine pathway, is inducible in APC and represents one of the main endogenous mechanisms of T cell homeostasis, peripheral tolerance and immunosuppression. No data have been published yet on the effect of α-GalCer on IDO in APC. We aimed to determine if: (1) α-GalCer modulates IDO in APC; (2) the α-GalCer-induced effect on IDO correlates with the production by APC of active compounds; (3) the medium from α-GalCer-treated APC is able to stimulate iNKT cells. From our results α-GalCer alone did not modify IDO expression (RT-PCR) in APC, but when human peripheral blood mononuclear cells (PBMC), monocytes, and monocytic cell lines (THP-1), expressing high levels of CD1d, were treated with interferon-γ (IFN-γ) plus α-GalCer a significant potentiation of IDO transcription was measured. This effect was not induced by increased IFN-γ release by APC, and it was functionally correlated with increasedl-kynurenine (l-KYN) release by α-GalCer-treated CD1d-transfected THP-1 cells. The medium of these cells stimulated iNKT hybridoma cells to release interleukin (IL)-2, while α-GalCer alone resulted ineffective. The data demonstrate that α-GalCer: (1) does not induce IFN-γ release by APC; (2) potentiates IFN-γ-induced IDO expression and function in APC; (2) requires CD1d molecules for inducing these effects; (3) induces the release by APC of compounds active in stimulating iNKT cells.

Keywords: Abbreviations; IDO; indoleamine 2,3-dioxygenase; α-GalCer; α-galactosylceramide; CD; cluster of differentiation; APC; antigen presenting cell; iNKT; invariant natural killer T cell; RT-PCR; reverse transcriptase PCR; PBMC; peripheral blood mononuclear cell; IFN-γ; interferon-γ; ELISPOT; enzyme-linked immunosorbent spot; l; -KYN; l; -kynurenine; IL; interleukin; MHC; major histocompatibility complex; TCR; T cell receptor; NK; natural killer; DC; dendritic cell; TLR; Toll-like receptors; NF-κB; nuclear transcription factor-κB; MAPK; mitogen-activated protein kinase; ERK; extracellular-signal-regulated kinase; JNK; c-Jun NH(2)-terminal kinase; TNF; tumor necrosis factor; iNOS; inducible nitric oxide synthase; NOD mice; non-obese diabetic mice; JAK; Janus kinase; STAT; signal transducers and activators of transcription; LPS; lipopolysaccharide; FBS; fetal bovine serum; mAb; monoclonal antibody; β-GalCer; β-galactosylceramide; α-ManCer; α-mannosylceramide; l; -KYNA; l; -kynurenic acid; TCA; trichloroacetic acid; 1-MT; 1-methyl-tryptophan; RA; retinoic acid; CTLA4; cytotoxic T-lymphocyte antigen 4; PGE; ₂; prostaglandin E; ₂; IRF-1; interferon regulatory factor-1; AP; activating protein; GPR35; G-protein-coupled receptor 35Glycolipid; Monocytes; iNKT cells; IFN-γ; l; -Kynurenines

Contribution of α₄β₁ integrin to the antiallergic effect of levocabastine by Ahmed R. Qasem; Claudio Bucolo; Monica Baiula; Antonino Spartà; Paolo Govoni; Andrea Bedini; Domenico Fascì; Santi Spampinato (pp. 751-762).

Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist. In allergic conjunctivitis (AC), it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. The adhesion molecule integrin α₄β₁ is expressed in eosinophils; it interacts with the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) in vascular endothelial cells and contributes to eosinophil activation and infiltration in AC. This study provides evidence that in a scintillation proximity assay levocabastine (IC₅₀ 406μM), but not the first-generation antihistamine chlorpheniramine, displaced¹²⁵I-FN binding to human integrin α₄β₁ and, in flow cytometry analysis, levocabastine antagonized the binding of a primary antibody to integrin α₄ expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the α₄β₁ integrin and prevents eosinophil adhesion to VCAM-1, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects α_Lβ₂/ICAM-1-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of α₄β₁ integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in AC.

Keywords: Abbreviations; AC; allergic conjunctivitis; BIO-1211; (; N; -[[4-[[[(2-methylphenyl)amino]carbonyl]amino]-phenyl]acetyl]-; l; -leucyl-; l; -aspartyl-; l; -valyl-; l; -proline); CMFDA; chloromethylfluorescein diacetate; EPR; early-phase reaction; FACS; flow cytometry analysis; FBS; fetal bovine serum; FITC; fluorescein isothiocyanate; FN; fibronectin; HBSS; Hank's balanced salt solution; HUVEC; human umbilical vascular endothelial cells; ICAM-1; intercellular adhesion molecule-1; LFA-1; leukocyte function-associated antigen-1; LPR; late-phase reaction; MFI; mean fluorescence intensity; PMSF; phenylmethanesulfonyl fluoride; PSA; ammonium persulfate; PVT; polyvinyltoluene; SDS-PAGE; sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SPA; scintillation proximity assay; TEMED; N; ,; N; ,; N; ′,; N; ′-tetramethylethylenediamine; VCAM-1; vascular cell adhesion molecule-1; VKC; vernal keratoconjunctivitis; VLA-4; very late antigen-4α; ₄; β; ₁; Integrin; VCAM-1; Cell adhesion; Inhibitor; Levocabastine; Allergic conjunctivitis; Eosinophil

The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan by Anna Alonen; Moshe Finel; Risto Kostiainen (pp. 763-772).

Losartan, candesartan, and zolarsartan are AT₁ receptor antagonists that inhibit the effect of angiotensin II. We have examined their glucuronidation by liver microsomes from several animals and by recombinant human UDP-glucuronosyltransferases (UGTs). Large differences in the production of different glucuronide regioisomers of the three sartans were observed among liver microsomes from human (HLM), rabbit, rat, pig, moose, and bovine. However, all the liver microsomes produced one or two N-glucuronides in which either N1 or N2 of the tetrazole ring were conjugated. O-Glucuronides were also detected, including acyl glucuronides of zolarsartan and candesartan. Examination of individual human UGTs of subfamilies 1A and 2B revealed that N-glucuronidation activity is widespread, along with variable regioselectivity with respect to the tetrazole nitrogens of these sartans. Interestingly, UGT1A3 exhibited a strong regioselectivity towards the N2 position of the tetrazole ring in all three sartans. Moreover, the tetrazole- N2 of zolarsartan was only conjugated by UGT1A3, whereas the tetrazole- N1 of this aglycone was accessible to other enzymes, including UGT1A5. Zolarsartan O-glucuronide was mainly produced by UGTs 1A10 and 2B7. UGT2B7, alongside UGT1A3, glucuronidated candesartan at the tetrazole- N2 position, whereas UGTs 1A7–1A10 mainly yielded candesartan O-glucuronide. In the case of losartan, no O-glucuronide was generated by any tested human enzyme. Nevertheless, UGTs 1A1, 1A3, 1A10, 2B7, and 2B17 glucuronidated losartan at the tetrazole- N2, while UGT1A10 also yielded the respective N1-glucuronide. Kinetic analyses revealed that the main contributors to losartan glucuronidation in HLM are UGT1A1 and UGT2B7. The results provide ample new data on substrate specificity in drug glucuronidation.

Keywords: Losartan; Candesartan; Zolarsartan (GR117289); UDP-glucuronosyltransferases; Substrate specificity; Tetrazole

Hepatic and extra-hepatic metabolic pathways involved in flubendazole biotransformation in sheep by Laura Maté; Guillermo Virkel; Adrián Lifschitz; Mariana Ballent; Carlos Lanusse (pp. 773-783).

Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound used in pigs, poultry and humans. Its potential for parasite control in ruminant species is under investigation. The objective of the work described here was to identify the main enzymatic pathways involved in the hepatic and extra-hepatic biotransformation of FLBZ in sheep. Microsomal and cytosolic fractions obtained from sheep liver and duodenal mucosa metabolised FLBZ into a reduced FLBZ metabolite (red-FLBZ). The keto-reduction of FLBZ led to the prevalent (∼98%) stereospecific formation of one enantiomeric form of red-FLBZ. The amounts of red-FLBZ formed in liver subcellular fractions were 3–4-fold higher ( P<0.05) compared to those observed in duodenal subcellular fractions. This observation correlates with the higher ( P<0.05) carbonyl reductase (CBR) activities measured in the liver compared to the duodenal mucosa. No metabolic conversion was observed following FLBZ or red-FLBZ incubation with sheep ruminal fluid. Sheep liver microsomes failed to convert red-FLBZ into FLBZ. However, this metabolic reaction occurred in liver microsomes prepared from phenobarbital-induced rats, which may indicate a cytochrome P450-mediated oxidation of red-FLBZ. A NADPH-dependent CBR is proposed as the main enzymatic system involved in the keto-reduction of FLBZ in sheep. CBR substrates such as menadione and mebendazole (a non-fluoride analogue of FLBZ), inhibited this liver microsomal enzymatic reaction, which may confirm the involvement of a CBR enzyme in FLBZ metabolism in sheep. This research is a further contribution to the understanding of the metabolic fate of a promissory alternative compound for antiparasitic control in ruminant species.

Keywords: Abbreviations; BZD; benzimidazole; FLBZ; flubendazole; red-FLBZ; reduced flubendazole; h-FLBZ; hydrolysed flubendazole; ABZSO; albendazole sulphoxide; MBZ; mebendazole; CBR; carbonyl reductase; P450; cytochrome P450 system; CYP; cytochome P450 subfamily; FMO; flavin-monooxygenase; PB; phenobarbital; MEN; menadione; QRC; quarcetin; WRF; warfarin; PBO; piperonyl butoxideFlubendazole; Anthelmintics; Biotransformation; Microsomes; Carbonyl reductase; Sheep

In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: A comparison with human liver microsomes by Luigi Quintieri; Marianna Fantin; Pietro Palatini; Sara De Martin; Antonio Rosato; Michele Caruso; Cristina Geroni; Maura Floreani (pp. 784-795).

We recently demonstrated that nemorubicin (MMDX), an investigational antitumor drug, is converted to an active metabolite, PNU-159682, by human liver cytochrome P450 (CYP) 3A4. The objectives of this study were: (1) to investigate MMDX metabolism by liver microsomes from laboratory animals (mice, rats, and dogs of both sexes) to ascertain whether PNU-159682 is also produced in these species, and to identify the CYP form(s) responsible for its formation; (2) to compare the animal metabolism of MMDX with that by human liver microsomes (HLMs), in order to determine which animal species is closest to human beings; (3) to explore whether differences in PNU-159682 formation are responsible for previously reported species- and sex-related differences in MMDX host toxicity.The animal metabolism of MMDX proved to be qualitatively similar to that observed with HLMs since, in all tested species, MMDX was mainly converted to PNU-159682 by a single CYP3A form. However, there were marked quantitative inter- and intra-species differences in kinetic parameters. The mouse and the male rat exhibited V_max and intrinsic metabolic clearance (CL_int) values closest to those of human beings, suggesting that these species are the most suitable animal models to investigate MMDX biotransformation. A close inverse correlation was found between MMDX CL_int and previously reported values of MMDX LD₅₀ for animals of the species, sex and strain tested here, indicating that differences in the in vivo toxicity of MMDX are most probably due to sex- and species-related differences in the extent of PNU-159682 formation.

Keywords: Nemorubicin oxidative metabolism; PNU-159682; Liver microsomes; CYP3A enzymes; Sex-and species-related differences

Astragaloside IV improves high glucose-induced podocyte adhesion dysfunction via α₃β₁ integrin upregulation and integrin-linked kinase inhibition by Jianguo Chen; Dingkun Gui; Yifang Chen; Lijun Mou; Yi Liu; Jianhua Huang (pp. 796-804).

Impaired podocyte adhesion to glomerular basement membrane (GBM) may contribute to podocyte detachment from GBM, which represents a novel early mechanism leading to diabetic nephropathy (DN). Here, we examined the effects of Astragaloside IV (AS-IV), a saponin purified from Astragalus membranaceus (Fisch) Bge, on high glucose-induced cell adhesion dysfunction in cultured mouse podocytes. Cells were seeded into 96-well plates coated with basement membrane protein complex (BMC). The cells were incubated for 12h in media containing 30mM glucose (HG) with 10, 50 and 100μg/ml of AS-IV. The cells were also exposed to HG media with 100μg/ml of AS-IV for 3, 6, 12 and 24h. Cell adhesion assays were performed by fluorescence and centrifugation methods, respectively. Levels of mRNA were determined by quantitative reverse transcriptase real-time PCR and protein expression was analyzed by immunoblotting. HG strongly inhibited adhesion of podocytes to BMC, accompanied by reduction in α₃β₁ integrin mRNA and protein expression, as well as increase in integrin-linked kinase (ILK) activity and expression. When podocytes under HG stimulation were treated with AS-IV, a dose- and time-dependent increase in cell–matrix adhesion was observed, which was significant from 10μg/ml of AS-IV and from 6h of incubation of AS-IV with 100μg/ml. This was accompanied by significant increases in α₃β₁ integrin mRNA and protein expression, as well as inhibition of ILK activation and overexpression. These results suggest that AS-IV improve HG-induced podocyte adhesion dysfunction, which is partly attributed to α₃β₁ integrin upregulation and ILK inhibition.

Keywords: Astragaloside IV; Diabetic nephropathy; Podocyte adhesion; α; ₃; β; ₁; integrin; Integrin-linked kinase

A common “hot spot” confers hERG blockade activity to α-scorpion toxins affecting K⁺ channels by Yousra Abdel-Mottaleb; Gerardo Corzo; Marie-France Martin-Eauclaire; Honoo Satake; Brigitte Céard; Steve Peigneur; Praveen Nambaru; Pierre-Edouard Bougis; Lourival D. Possani; Jan Tytgat (pp. 805-815).

While α-KTx peptides are generally known for their modulation of the Shaker-type and the Ca²⁺-activated potassium channels, γ-KTxs are associated with hERG channels modulation. An exception to the rule is BmTx3 which belongs to subfamily α-KTx15 and can block hERG channels. To explain the peculiar behavior of BmTx3, a tentative “hot spot” formed of 2 basic residues (R18 and K19) was suggested but never further studied [Huys I, et al. BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K⁺ and HERG currents. Biochem J 2004;378:745–52].In this work, we investigated if the “hot spot” is a commonality in subfamily α-KTx15 by testing the effect of (AmmTx3, Aa1, discrepin). Furthermore, single mutations altering the “hot spot” in discrepin, have introduced for the very first time a hERG blocking activity to a previously non-active α-KTx.Additionally, we could extend our results to other α-KTx subfamily members belonging to α-KTx1, 4 and 6, therefore, the “hot spot” represents a common pharmacophore serving as a predictive tool for yet to be discovered α-KTxs.

Keywords: hERG channels; Scorpion toxins; K; ⁺; channels; α-KTx; γ-KTxs

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Biochemical Pharmacology (v.76, #6)