‘Available online at www.sclencedirectcom Biochemical Pharmcsony 65 (2008) 1085-1061 Commentary Multidisciplinary utilization of dimethyl sulfoxide:pharmacological, cellular, and molecular aspects Biochemical Pharmacology ELSEVIER ‘wonelvicconvoeseboskempbam Nuno C. Santos”, J. Figueira-Coelho, J. Martins-Silva, Carlota Saldanha Instnao de Bioginicastintn de Medicina Molecule, Faculdade de Medicina de Lisboa, hx. Prof, Bgas Moni, P-1649-028 Lisha, Portugal Abstract ‘DMSO is an amphipathic molecule witha highly polar domain and two apolar methyl groups, making it soluble in both aqueous and ‘organic medi, Ii one of the most common solvents forthe in vivo administration of several water-insoluble substances, Despite being frequently used asa solvent in biological studies and as a vehicle for drug therapy, the side-effects of DMSO (undesirable for these Purpose) are apparent from its utilization in the laboratory (both in vivo and in vito) and in enical settings. DMSO isa hydrogen-bound disrupter, cell-lfferentiting agent, hydroxyl radial avenge, intercellular electrical uncouper, niacelular low-density lipoprotin- ing agent, cryoprotectant, solubilizing agent used in sample preparation for electron microscopy, antidote to and topical analgesic, Additionally, its used in the treatment of brain edema, amyloidosis, interstitial cysts, and schizophrenia, Several systemic side-effects from the use of DMSO have been reported, namely nausea, vomiting, dliarhea, hemolysis ashes, renal failure, hypertension, bradycardi, heart block, pulmonary edema, cardiac ares, and bronchospasm, Looking atthe mulitude of effects of DMSO brought to light by these studies, itis easily understood how many researchers working with DMSO (or studying one ofits specific effecs) might note fully aware of the experiences of ether groups who are working with it but in a different context. |© 2008 Elsevier Science Ine. All rights reserved. ‘Keywords: Dime sulfide; Amylidsis Inflammation; Call eee: Cail diferentaton; Cryopresenstion 1. Introduction DMSO {(CH;).S0] is an amphipathic molecule with a highly polar domain and two apolar groups, making it soluble in both aqueous and organic media. Due to these physico-chemical properties, DMSO is a very efficient solvent for water-insoluble compounds and is a hydro- gen-bound disrupter (see Ref, [1], for example). Despi being known since the nineteenth century (mainly due to its use in the wood industry), its biologie properties were only discovered in the 1960s. Since then it has been used for diverse laboratory and clinical purposes. DMSO is fre- quently used as a solvent in biological studies and as a vehicle for drug therapy. However, its side-effects (unde- sirable for these studies) are often neglected. In this article, we will try to present a global insight over the molecular, cellular, pharmacological, and toxicological effects of DMSO. * Corespoading author. Te +31-21-7985136, fax: 1351217939791 ‘moll adres: nets @fnl pt (NC. Sant). 2, Pharmacological applications of DMSO DMSO has been used in several human therapeutic situations. In 1978 it received approval by the United States Food and Drug Administration (FDA) for use in the treatment of interstitial cystitis, by intravesical instilla- tion [2]. Its effects do not seem to be related to adetectable histamine release from mast cells (3]. It has been used successfully in the weatment of dermatological [4-6], urinary [7], pulmonary [8], rheumatic and renal (9] man- ifestaions of amyloidosis. Basically through its anti- inflammatory and reactive oxygen species scavenger actions, its use has been purposed in several gastrointest: inal diseases [10-14]. DMSO crosses the blood-brain barrier [15] and has been effective in the treatment of traumatic brain edema [16]. It has been also used in the treatment of musculoskeletal disorders [17], pulmonary adenocarcinoma (18), rheumatologic diseases. [19,20], chronic prostatitis [21], dermatologic diseases [22-24], schizophrenia [25], and as a topical analgesic [26]. In addition, it has been suggested for the treatment of Alz~ hheimer’s disease [27]. Some of the reported effects of 006.2952 - sce font mater © 2003 Elsevier Sconce Ic. Al igh reserved, soi:10 1010006 2952(03)00002:9106 [N.Sants el /Blochomcal Pharmacology 6 2003) 1035-1041 ‘Tibie 1 Bef sumary ofthe reported eects of DMSO in he tant of diferent human and experimental animal mode diseases Disease ‘Actonsietets efeencet) Total ein Tiproves estes, ot heeft ot elated with mast oll ease ofstnine ea Amloidoss eps ocontol pastas in macular and chen amplodos, avoiding the recent depoion of [4] smo nares of tau ofthe epidermis. {Cases egesio of yan depose in pid protlasis oy Improves primary amyloidosis ofthe blader (aston) a Redoes pulmonary inition sod improves aerial blood gas levels in pulmonary amyloidosis 8) sociated wth mule ayeloenn eed inthe eatment of some eases of primary amyloidosis when combined with es) yore chemotherapy Tnces x decese ofthe ifamatory activity of Females and an improveneat “1 ‘ot rena function following 3-6 months of therapy a pains with secondary anos Induces growth ad blackish tun of sap bai and beard Gasrvnteinal disorers Hasan antammatry fect in wceriveeoits tuo} Asoc with H,reepor blockers, mare eat for eaing acute duodenal wleeration wu) te prevention ofits eeurence tan Hy sep blockers alone Improves survival in pains bering colo carcinoma 2 ast Geet therapete effect inthe mechanism of abdominal pin caused by alcoboLindued 113) aoa pancreatitis (Gives protection in seesinduced cue gaste mucosal inary va Bin ede as «beneficial ffs inthe trestment of eaatie baa ema 61 Rcunsiologc disorders Has benef fet in the ueatneat of rheumatoid atts, edi the associated pin roy Enhance he eff of gsocorcoids in the treatment of sheumaoid synovitis 0 Cheon ratatis Induces «postive result in he treatment of human ernie posta en Schizophrenia Has an atipyebi ction es, Primonary adenocarcinoma groves the antilifrive eet of interferon human lng adenocarcinoma cells as throu an ance mechanism Dermatologic disorders asa beet elect i he topical treatment of herpes ater a2 Enhance the efaey of fngicie inthe Westen of domatcogic mycoss ps} Inan effective and safe stidte that may be used with local cooling afer the extivaston of cerxin [24] rap sed in chomothrpy lve inravenost,peveatng the nseons of tens and lceration [Experiment animal model nbs eollagan a gene expression, increate nse collagen cota, hepatic sella cell 091 tctvaton, yates ftisse inhibitors of melloprtiase-2 and, conreqealy, the development flv into a mice Prevent the development of liver cinhoss induced by tioned po) DMSO jin the treatment of different diseases are summar- ied in Table 1 ‘Besides all ofthe previously referred to pharmacological applications in the treatment of different pathologies, several systemic side-effects from the use of DMSO have been reported, namely nausea, vomiting (30), diarrhea {G1}, severe hemolysis mimicking a hemolytic transfusion reaction 32], anaphylactic reactions manifested by rashes, flushing, and (occasionally) bronchospasm [33,34], renal failure (35) diastolic and systolic hypertension [36], bra- dycardia, heart block [37-39], and (rarely) pulmonary cedema or cardiac arrest [40,41]. A significant side-effect ‘of DMSO isa garlic-like breath odor and taste in the mouth due to the pulmonary excretion of a small percentage of, DMSO as dimethyl sulfide [42]. Its topical application, although well tolerated, can cause mild transient local ‘burning [24], skin rash, and pruritus [22]. A case of sulfhemoglobinemia after dermal application of DMSO inthe treatment of interstitial eysitis has been reported, ‘with fatigue, cyanosis, and dyspnea with mild exertion [4] ‘Serum hyperosmolality in the control of increased intra- cranial pressure with DMSO given intravenously has also bbeen described [43]. This expected effect was also ‘observed in human blood in vitro studies [44]. However, DMSO penetrates the cell membrane and causes an increase in osmolality both inside and outside the cell, preventing any significant hemolysis due to the formation ‘of an osmotic gradient [45] 3 Cellular and molecular effects of DMSO Zhang and Eyzaguirre [46] reported that the rise in intracellular calcium concentration induced by hypoxia in mouse glomous cells is blunted by the presence of DMSO. The studies of Choi er al. [47] with human promyelocytic leukemia HL-60 cells also. indicated that the neurotensin-induced rise in intracellular [Ca**)NC. Sams et a /Bachemiol Pharmacology 65 (2003) 1035-1041 1037 disappeared after weatment with DMSO. Michel [48] showed that in DMSO-treated human erythroleukemia cells, calcium elevations by adrenaline and neuropeptide Y were reduced significantly. Finally, Reynaud et al [49] reported a similar DMSO interference withthe hepox- ilin As effect on human neutrophils. These four recent findings are in accord with our observation that DMSO prevents the ionophore-induced calcium loading of human erythrocytes [44]. This coherence between results obtained action of DMSO, disabling the expected effect of the modulator. Tn the same study [44], we showed that there is an increase in the extracellular concentrations of K*, Na‘, and Ca** in whole blood aliquots incubated with DMSO. (2%, vis). These findings are probably due to a DMSO- induced leakage of ions from human platelets, an effect that does not alter the plasma pH significantly (50). AC the molecular level, an explanation forthe effect of DMSO on intracellular and extracellular ion concentrations is pre- vented by the divergence in the published studies of the with different biological systems and different modulators of the rise in intracellular [Ca?*] suggests a nonspecific ‘Tble2 Bret summary ofthe reported effets of DMSO in the study of the inflammation process, chseed in experimental models tones References) Tenis imreukn 8 paducon na dose-dependent mane, dry tte tanserptoal evel Prevents adeson of auuopbls 57] 'o endotetum, Ssavenges C1O~ and posly reduces NADPH -ouide activity ibis human plate agreaton induced by ADP, rchionic acid (AA), plate acivaing factor (PAF) nd ose, ina (58) coocenvaondependen manne, being a oe elective inhibitor for agaepation indeed by ADP and cllages than PAF or AA Stimines prstaglntin E, and IZ HETE (hyronyeicossetzenic acid) production by bovine seminal vesicle prostaglandin sybase, 158] dint the production oft HETE produce vi the Iipoxygenase paths Ices dacese in prteolycan synthesis in a ime dependent manner dehation of the crage al chondrocyte death 13940) auine joiats show decrease in synovial eocyte eos, educed infsmuatoryresjons, and spre max metabo Ini episindoed activation of clea factor-xB (NF), resting inthe suppression of itecellar adhesion molecule oy TICAM) gee expression i he ies of pent epi rats Enhances hana clomegalovins replication by upepulting the major immo ealy promote, n pat, aed 1 enhanced 2) [NFA and elie AMP response element Bnding protein sti Potties tumor ners factor (TNF-3)-indaced eyotoicty in various human myeloid cel Hines {s6) Decreases the leel of NFxB aciation ins macopgelike ell ne, cored with decreased expen of eytokine messenger [63] [RNA and TNF-boscvity, suggesting tat modulation of NFB activation may provide a mectanism tough which anoxia protect gaat endotoxemia in marine models hance he production of Several pateletspecicproting, ite factor 4, and platelet activation dependent granule extern 1 membrane protein Inhibits formytmathiony-eucy-pbenlanin (MLP) and leukotriene Brinda leakosye adherence in a doserelatod manner in (65) 1a colon vnulr endothelin ‘ables Brit summary ofthe eported eects of cll yl, fferentintion, and apoptosis nies, csered in experimental mode Type of udy _Acionvetecs Reference) ‘Cen ele Inhibits mye expression, in diteear cell pes (66-68), Int empe expression daring the G oS tanston in adherent ible el areed at Gay Io by serum stration Ares the cll yee of sever hums and mous yp cline tthe G, phase ro Ares the cll ee of «transformed huntn B-cell le at , phase and eappeses nteroukn-6 indeed mm ‘ierensinion nto IgM prodacng cells a a concentration lower tan that affecting cll proliferation, sopgsting that cel proiesion and dfremition ae independ ofeach other Ditfetition Downrepultes e-mye prot in the Gyo specie phase prior wo the appearance of difereniaonasocated markers [72] May inde difleretstion of malignant cls preset nthe marrow or aleraively inthe Body when ii infused (73) ‘ack with he trasplanted marow Enhances the dferentstion of lakes clls to mate myloeytes v4) ‘Prevents dediterenation of mal cls, Caled adit rat heptoeytes canbe maintined and made to seers (75) sltumin fr more than 40 days Leads tothe cesston ofthe proliferation of murine erytuolekemia cells nd the production of « numberof 81 ceytroeyte marker, such a5 Hemoglobin ‘Apoptosis Leas to he calls of mitochondrial membrane poset lease of estrone rom the mitoehondia, and (77 scvation of easpse9 and 3, but not of easpase (caspase easade of mitochon apoptotic alway is Ingispensable for DMSO‘duced spptoss). Induces pop changes in a morineIymptoma celine (Concentration: and tne. dependent effet) and dowr-epalaton of Bek Prevents opts i mpona cls v81038 [NC Santor et Biochemical Pharmacology 6 (2003) 1035-1041 cffects of this solvent on transmembrane ion transport mechanisms. A DMSO-induced reduction of Ca™ efflux ‘was described for dorsal root ganglion cells from neonatal rats (51) and for skeletal muscle, cardiac muscle, and cerebellar vesicles [52], AC variance, the studies of Ogura et a. [53] with guinea pig ventricular myocytes indicated that incubation with DMSO had ltl effect on Ca* and inward-reetifer K* currents, moderately inhibited CI” and Na* curents, partially inhibited the Na” pump curren, and markedly depressed the delayed-tectiier K* current. The date found in the literature for ATPase activities is again by DMSO [54,55]. Using human erythrocyte ghosts and the ‘same range of DMSO concentrations, McConnell et al. [56] showed that DMSO inhibits calmodulin-stimulated (Ca?* + Mge*)-ATPase and (Na* + K*)-ATPase, without any significant effect on calmodulin-independent (Ca** + ‘Mg?*)-ATPase and on Mg"*-ATPase activites. ‘These and othe reported cellular and molecular effects ‘of DMSO (such as diferent effects related to inflamms- tion, lipid metabolism, apoptosis, cell cycle, protein expression, differentiation, molecule binding, enzyme activity, reactive oxygen species scavenging, cell polriza- controversial. Different authors have reported an activation tion, cryopreservation, and other experimental procedures) of purified erytroeyte membrane (Ca®* + Mg?*)-ATPase are summarized in Tables 2-5. es Brief summary of he reported effects of DMSO in lipid metabolism ad other sues, observed in experimental moses “ype of say pid mei ‘Aatoeltects Reference “Activate aid phingomyeinse and welts te inact mobilation of low density ipptin = (LDU) derived cboesteat Tacreues th tafe of uneterifed chester between membranes (80) Prevents the expected rein serum cholesterol by SOS, bu docs not prevent cholesterol accumulation ia 81) tot ssc, whe administered in the inking wate of cholesterol-fed eockerels Reverse the sboomal processing of LDL choleserel in mutans Niemasn-PickdzesseRbrbinss, 3) ‘nly the exenineIsneomal accumulation of LDL coleteol td the delayed induction of ella omeoeate responses anointed withthe uptake of LDL by the mutant col, Accelerates the ‘ntscelsr mobilization of LDL deve cholestrol trough effacts ht may rect enhanced ‘membrane pemesbliyorchletrlsluillzton. Amliortes a secondary deficiency of ‘hingomyelinse actity tha can be presen in tee robles a manifestation induced by excesve LDL cholesterol tht acumlates in the ysosomes ofthe els Redes the acomusion of cholestrol in vsclar and extravascular sss, and partly 3) preven the developmen of ditay colesieorinduced atherosclerosis (espe the severe Iypercholsteroemia accompanying the cholesterlfedig), when administered in the dining site feb Reduces the binding, lotemaliatio, and degradation of exogenous LDL inhuman skin cured Girbless: (83) ot acting by inereasng te secretion of chester! by the el Otter Suppress the expression of CD20 m Enhances the expression of yt Lewis and slay dimeric Lowe antigens om the wrface of human te ‘asic earcinoma col, andthe binding of Linus polyphemus aggltinin (which specially binds 0 ‘all-suface alic ) ‘Modis the protein conformatic of matt pS to one recognized bya wildype specie monoclonal 18) ibd in murine erytrleukemi elie, accompanied by translocation ofthe pS proin from the otoplaam othe clea Increase the fess af band 3 protein without noticeable changes inthe synthesis of ether membrane (861 poten eythopoiin-induced erytaoi cls [Enhances and mantis thyrod fection fr more than 13 day, with evidence of de noo sates and 7 ‘elas of thyroid bommones, when added oth sul cate median to preserve human tyroyes extracted from pants with Graves disease DDeseasespsoeaminglyean chain length i oman enttolekemi ell potogycans ioe ‘Decreases human erytroeyteageepition inser and ead 0 higher plasma concentrations of K", Nat (44) and ce Protects against I-nethy--pheaylpyrdinium (MP") toxicity though the inkition of OH radea-mediated 88] ‘oxidative inary inthe substantia nigra "as pov ano agave lnowope effects on perused hea and scat cardiac tise preparations. 3) Depress nerve condoston velocity and affects enzymatic acti rated to Na*purmpig, scond ‘mesengeprodusion, and mitochondria oxidative phosphoylaica Is fe radical scavenger, poten Linas C activator, and myocar couture reaxant 3) ‘locks yaminobutyresidsiniced CI eae in rt dona oot pnglion aeons 153) Canes» small hyperolacation and rlongiton ofthe acon potetal of gina pig papillary muscles 53] Hla inotropic and chronotropic elect alec various ATPase end protects the eat agin isco jury (89) Tabi he binding of prostaglandin F,, 1 coer lea ell membranes 13) ‘Ales the pemeablty and ality of Iyesomal membranes im (2) Induces an increase of itracelsie[C3], dependent upon exacollar (Ce) in dispersed ovine cls (90) ‘nd cll slated rom human patyrld adenomasNC. Santos ea. Biochemical Pharmacology 65 (2008) 1035-1041 1039 “ables ef summary of the reported effets of DMSO in sme ofits technica plications mien ‘ations Referee Coropreeraton ‘On the cryopresertion of haman plates, induces KY, Ca*, al actatedeydrogenae release (S01 from te naclsar space othe extrcllalar pace, and strongly ates complement ‘Atmoderateconenztion, preserves the str of he smiaferous epithe of rat etl biopsies (91) [AC LSM. allows th enopreeration of tunan ies with sopeir survival and preservation of 21 poster fonction, when compared wih 20M or diferon eyes glyel concentrations “ogater wih a could rat of fezing agely prevents te celular damage in iering, caused 3) ty the frmaton of ce ental within the els ‘A ial concenton ofS (vy) a atologs ples, without urteradtves, is saiet for 94) ‘Syopreervation of cord Mood stm ceils x banking routine ‘Prevent dumage in hemopoietic nem cells, dang cryopreservation es Otte procedues Preseate&hydrogen-bounddisrion ston m Due tis song scinenging effects, should teased wih aun a soventinchemilminescence [96] sti. Concentrations blow 156 (9) do ot intefee wit tbe results hance the penetration of chemicals and sade ofatives wo inpove cll reservation. At fw in oneetations, nase abd cxmm-dchomate faves fr electon microscopy, the laste tnd cellar dts chive good preservation ‘AC 1% (of), enbanes the perma dlivery of DNA to human beast tumor cells (98) Decrees hei iro bind of bidium vo DNA 31 4, Summary Looking at the multitude of effects of DMSO brought ‘out in this commentary, it is easily understood how many researchers working with DMSO (or studying one of its specific effects) can be unaware of the results of other ‘groups working with itin a different context, The absence of a complete understanding of the effects of DMSO can preclude the reaching of accurate conclusions, since experimental artifacts caused by DMSO can lead to the erroneous interpretation of results. We believe that an increased awareness of the multidisciplinary utilization ‘of this molecule in several research fields can be a valid contribution in order to avoid or minimize these problems. Acknowledgments ‘This work was partially supported by the Fundagio para 44 Cigncia e Tecnologia (FCT) and by the Calouste Gul- bbenkian Foundation (Portugal). References {1} Somos NC, Pito MUE, Moms-Gomes A, Betbeder D, Castano “MARE, Stuctural chrcerizatio hae aod dimeusions) and ste bility of polyeacsharideipid nanoparticles. Blopalymes 19974 siL-20 (2) Parkin J, Soa C, Sant GR. Inravesial dimethyl slfexid (D350) for intial eysitis—aproctical approach, Urology 1997481057 [3] Stout L, Gexgach IM, Levy SM, Yan SK, Lad PM, Leach GE, inners PE. Dimethyl sulfxide doesnot tigger rine histamine relat in iter etis. Urology 195:46 653-6 (6) Borg JL, Hamner AP Roberson WO. 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