Kinetics and mechanistic studies of the hydrolysis of diisocyanate-derived bis-thiocarbamates of cysteine methyl ester

Diisocyanates (dNCOs) are the most commonly reported cause of chemically induced occupational asthma, but the ultimate antigenic form is unknown. Reactions of the three most common monomeric dNCOs, hexamethylene dNCO (HDI), methylene diphenylisocyanate (MDI), and toluene dNCO (TDI), with cysteine methyl ester (CME) gave the corresponding bis-dithiocarbamates (HDI-CME, TDI-CME, and MDI-CME). The dissociation kinetics of these bis-thiocarbamates, in aqueous conditions, was followed spectrophotometrically under varying pH and temperature conditions. Reaction of the adducts with methylamine or human serum albumin (HSA) produced diurea, monourea, and diamine products, and this was consistent with the base-catalyzed elimination reaction (E1cB) pathway being the dominant, but not exclusive, dissociation mechanism. The hydrolysis of the adducts was first-order with respect to OH(-) concentration and overall second-order (HDI-CME, k = 3.36 x 10(2) M(-)(1) min(-)(1); TDI-CME, k = 2.49 x 10(4) M(-)(1) min(-)(1); and MDI-CME, k = 5.78 x 10(4) M(-)(1) min(-)(1) at pH 7.4) with deviation from second-order when the dNCO had an aromatic functional group. Arrhenius plots gave activation energies (HDI-CME, E(a) = 70.6 kJ/mol; TDI-CME, E(a) = 46.1 kJ/mol; and MDI-CME, E(a) = 44.5 kJ/mol) that were consistent with the following order of stability: HDI-CME > TDI-CME > MDI-CME. Therefore, the stability of different dNCO-derived thiocarbamates in aqueous environments can vary greatly. Thiocarbamate dissociation rates and type of products formed may potentially influence antigenicity and subsequent hypersensitivity/toxic reactions following dNCO exposures.     

The effects of glycine and L-arginine on heat stability of ginsenoside Rb1

To identify the effects of amino acids on the heat stability of ginsenoside Rb(1) (Rb(1)), Rb(1) was heat-processed at 120 degrees C with or without glycine or L-arginine. Rb(1) was changed into 20(S)-Rg(3), 20(R)-Rg(3), Rk(1), and Rg(5) by heat-processing through glycosyl elimination and epimerization of carbon-20 by SN1 reaction. Similarly, Rb(1) was changed into 20(S)-Rg(3), 20(R)-Rg(3), Rk(1), and Rg(5) when it was heat-processed with the same amount of glycine, but the generated amount of 20(S)-Rg(3) was higher than when Rb(1) was heat-processed without amino acids, and a significant increase in Maillard reaction products (MRPs) was noted. On the other hand, there were no structural changes in Rb(1) and the generation of MRPs when Rb(1) was heat-processed with the same amount of L-arginine. The improved heat stability of Rb(1) brought about by the addition of L-arginine was thought to be closely related to its characteristics of interfering with nonenzymatic glycation and forming hydrogen bonds with Rb(1).     

In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates

The in vitro characterization of the inhibition potential of four representative maytansinoid species observed upon hepatic and/or tumor in vivo processing of antibody-maytansine conjugates (AMCs) with cleavable and noncleavable linkers is reported. We investigated the free maytansinoid species N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), (S)-methyl-DM1, and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) as representative cleavable linker catabolites and Lysine-N(ε)-N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate-DM1 (Lys-MCC-DM1) as the representative noncleavable linker catabolite. Studies with recombinant human cytochromes P450 (P450s) indicate CYP2D6, CYP3A4, and CYP3A5 are the primary isoforms responsible for the oxidative metabolism of DM1, (S)-methyl-DM1, and DM4. Lys-MCC-DM1 was not metabolized by any of the P450 isoforms studied. DM1 was shown to be a reversible inhibitor of CYP2C8 (K(i) = 11 ± 3 μM) and CYP2D6 (K(i) = 14 ± 2 μM). Lys-MCC-DM1 and (S)-methyl-DM1 showed no reversible or time-dependent inactivation of any of the P450s studied. DM1 and DM4 inactivated CYP3A from human liver microsomes with K(i)/k(inact) values of 4.8 ± 0.9 μM/0.035 ± 0.002 min(-1) and 3.3 ± 0.2 μM/0.114 ± 0.002 min(-1), respectively. DM1 and DM4 inactivated recombinant CYP3A4 with K(i)/k(inact) values of 3.4 ± 1.0 μM/0.058 ± 0.005 min(-1) and 1.4 ± 0.3 μM/0.117 ± 0.006 min(-1), respectively. Because of instability in plasma, further characterization of the DM1 and DM4 intramolecular and intermolecular disulfide conjugates observed in vivo is required before an accurate drug-drug interaction (DDI) prediction can be made. AMCs with noncleavable thioether-linked DM1 as the cytotoxic agent are predicted to have no potential for a DDI with any of the major human P450s studied.     

Molecular mechanisms of vasoselectivity of the 1,4-dihydropyridine lercanidipine

The effects of (S)- and (R)-lercanidipine on CHO cells stably expressing the cardiac (Ca(v)1.2a) or vascular (Ca(v)1.2b) splice variant of the L-type calcium channel pore subunit were studied, using whole-cell and single-channel patch-clamp measurements. Lercanidipine block of Ca(v)1.2b current was enantioselective. (S)-lercanidipine was 4.1-fold more potent. Experiments using acidic solutions (pH 6.8) revealed a 6.4-fold enhanced inhibitory effect of (S)-lercanidipine compared with physiological conditions (pH 7.4) indicating that the charged form mediates inhibition. At depolarised holding potential (-40 mV), (S)-lercanidipine exhibited a 35-fold greater potency, compared with standard conditions (-80 mV). A comparison of the concentration-dependent inhibition of Ca(v)1.2a with Ca(v)1.2b subunit currents by (S)-lercanidipine revealed only a 1.8-fold difference in IC(50), but the slope of the dose-response curve was much steeper (n(H)=2.3) with Ca(v)1.2a, compared with Ca(v)1.2b (n(H)=0.8). This indicates overlap between agonistic and antagonistic effects, predominant with the cardiac Ca(v)1.2a subunit. This idea is supported by transient stimulatory effects, and a slight leftward shift of the IV curves. These effects were more prominent for Ca(v)1.2a than for Ca(v)1.2b. Single-channel experiments confirmed typical features of calcium channel agonists such as prolonged channel openings, a component of lengthened openings, and an enhanced open probability in the presence of (S)-lercanidipine. Again, these findings were concentration-dependent and more pronounced for Ca(v)1.2a than for Ca(v)1.2b. Our data indicate a splice-variant predominant agonism as a new mechanism contributing to the vasoselectivity of lercanidipine, along with marked voltage-dependence of action.     

法西多曲的合成

参照已知方法制得的2-乙氧羰基-3-(3,4-亚甲二氧基)苯基丙酸钾(6),用KBH_4/ZnCl_2选择性还原得2-羟甲基-3-(3,4-亚甲二氧基)苯基丙酸(7),再经葡辛胺拆分、双氯化得到的(R)-2-氯甲基-3-(3,4-亚甲二氧基)苯丙酰氯(8)与L-丙氨酸苄酯缩合后得N-[(2S)-2-氯甲基-3-(3,4-亚甲二氧基)苯丙酰基]-L-丙氨酸苄酯(9),与硫代乙酸钾反应得法西多曲,总收率约16%(以胡椒醛计)。其中2个中间体(8和9)为未见文献报道的新化合物。     

Effects of cooling on histamine-induced contractions of human umbilical artery: the role of ion channels

The effects of cooling (to 28 degrees C) on histamine (10(-9) - 3 x 10(-4) M)-induced contractions and the role of calcium (Ca(2+)), potassium (K(Ca) (2+)) and sodium (Na(+)) channel blockers in the cooling-induced responses were investigated in the endothelium-denuded human umbilical artery. Concentration-response curves to histamine were isometrically recorded at 37 and 28 degrees C (control). The same procedure was repeated at 28 degrees C in the presence of tetraethylammonium (TEA, 10(-3) M), pilsicainide (10(-6) M), ouabain (10(-6) M), caffeine (3 x 10(-4) M), verapamil (10(-6) M) and also in Ca(2+)-free medium with ethylene glycol bis-(beta-aminoethyl ether) N,N,N(1),N(1)-tetraacetic acid (EGTA). During cooling, the sensitivity, but not the maximal response, was significantly higher than 37 degrees C. Cooling to 28 degrees C after treatment with verapamil or pilsicainide decreased the sensitivity, whereas treatment with TEA and ouabain significantly increased sensitivity. Treatment with caffeine did not modify the effect of cooling. Furthermore, cooling to 28 degrees C after incubation in Ca(2+)-free solution with EGTA decreased the sensitivity to histamine. The results of this study suggest the role of Ca(2+), K(Ca) (2+) and Na(+)-ion channels in the cooling-induced changes of human umbilical arteries treated with histamine.     

奎扎替尼的合成

对硝基苯酚(2)与4-(2-氯乙基)吗啉盐酸盐(3)发生亲核取代反应得到4-[2-(4-硝基苯氧基)乙基]吗啉(4),4经10%钯炭氢化还原得到4-[2-(4-吗啉基)乙氧基]苯胺(5)。5经2步环化反应得到7-[2-(4-吗啉基)乙氧基]-2-(4-硝基苯基)咪唑并[2,1-b][1,3]苯并噻唑(8)。8经铁粉和氯化铵还原得到4-[7-[2-(4-吗啉基)乙氧基]咪唑并[2,1-b][1,3]-苯并噻唑-2-基]苯胺(9)。另以3-氨基-5-叔丁基异?唑(10)和氯甲酸苯酯反应得苯基(5-叔丁基异?唑-3-基)氨基甲酸酯(11)。用9与11反应得到奎扎替尼(1),终产物纯度为99.17%,总收率为55%(以2计)。该方法所使用起始原料2价廉易得,且3的用量大大降低,反应条件相对温和,后处理操作简便,可为工业化生产提供参考。     

Lack of effect of a single-dose of sulglicotide on the bioavailability of diclofenac

Summary The bioavailability of diclofenac (D) was assessed in 12 healthy volunteers treated orally with single doses of 100 mg (retard formulation) and subsequently retreated with the same dose of (D) plus sulglicotide (S) 200 mg.(D) blood levels were measured by GLC in samples collected after 1, 2, 4, 6, 8, 12, 24 h. No relevant difference was seen in (D) bioavailability after (S) administration; after 8 h plasma levels of (D) were slightly higher after (S) (p<0.05), but this difference can be considered incidental only. Thus, sulglicotide does not interfere with the bioavailability of diclofenac, and can be administered concurrently with the latter to prevent possible gastric injury by the antiinflammatory drug.     

利奈唑胺的合成

(S)-环氧氯丙烷(2)用叠氮钠开环得到(S)-1-叠氮基-3-氯-2-丙醇(3);另用3,4-二氟硝基苯(4)经与吗啉反应后以铁粉还原硝基,再与氯甲酸乙酯反应得到N-[3-氟-4- (4-吗啉基)苯基]氨基甲酸乙酯(7).3和7经环合反应制得(S)-3-[3-氟-4- (4-吗啉基)苯基]-5-叠氮甲基-1,3-噁唑烷-2-酮后,再经水合肼还原、氨基乙酰化得到抗菌剂利奈唑胺,总收率约40％(以4计).     

Application of fluorescence microscopy for investigation of cellular distribution of dinuclear platinum anticancer drugs

The dinuclear platinum complexes with aliphatic diamines [{cis-Pt(NH(3))(2)Cl}(2)(mu-H(2)N(CH(2))(6)NH(2))](NO(3))(2) (1,1/c,c) and [{trans-Pt(NH(3))(2)Cl}(2)(mu-H(2)N(CH(2))(4)NH(2))](NO(3))(2) (1,1/t,t), which are known to be highly active in vitro against several cancer cell lines, have been modified with a fluorogenic reporter (carboxyfluorescein diacetate, CFDA) and a hapten (dinitrophenyl, DNP). These labeled complexes have been designed for fluorescence microscopy investigation of cellular pathways of promising dinuclear platinum anticancer drugs and present the first example of labeling biologically active dinuclear platinum complexes with a fluorescent reporter. The modified compounds interact with a guanine model base similarly to the label-free parent complexes. The uptake of the complexes with a fluorescent label and the respective unlabeled complexes in the U2-OS human osteosarcoma cell line and its cisplatin-resistant derivative, U2-OS/Pt cell line has been investigated. Cellular processing of the CFDA- and DNP-modified dinuclear platinum complexes in U2-OS and U2-OS/Pt cells has been studied.     

腮腺区肿瘤的术式探讨

目的 分析腮腺区肿瘤的手术方式与肿瘤复发等术后并发症的关系.方法 对69例腮腺区肿瘤的病案资料进行回顾性分析.结果 69例腮腺区肿瘤中,术后复发1例(14%),出现面瘫16例(23%)、涎瘘8例(12%)、Frey症(出汗综合征)5例(7%).其中单纯瘤体摘除术(即剜除术)5例,术后复发1例(20%);肿瘤连同周围部分腮腺及淋巴结区域性切除术12例,术后出现面瘫2例(17%),1个月后自行恢复,涎瘘5例(42%),Frey症1例(8%);肿瘤+腮腺浅叶切除术+面神经饵剖50例,术后出现面瘫12例(24%),术后3～6个月恢复正常,涎瘘3例(6%)、Frey症4例(8%);肿瘤+腮腺全叶切除(保留面神经)术2例,术后出现面瘫1例(50%),术后3个月恢复正常,另1例为永久性面瘫(50%).结论 腮腺区肿瘤的术后复发等并发症与腮腺手术方式密切相关,严格掌握正确的手术方式可减少肿瘤的复发等并发症.     

Mechanisms of arsenic-induced prolongation of cardiac repolarization

Arsenic trioxide (As(2)O(3)) produces dramatic remissions in patients with relapsed or refractory acute promyelocytic leukemia. Its clinical use is burdened by QT prolongation, torsade de pointes, and sudden cardiac death. In the present study, we analyzed the molecular mechanisms leading to As(2)O(3)-induced abnormalities of cardiac electrophysiology. Using biochemical and electrophysiological methods, we show that long-term exposure to As(2)O(3) increases cardiac calcium currents and reduces surface expression of the cardiac potassium channel human ether-a-go-go-related gene (HERG) at clinically relevant concentrations of 0.1 to 1.5 microM. In ventricular myocytes, As(2)O(3) increases action potential duration measured at 30 and 90% of repolarization. As(2)O(3) interferes with hERG trafficking by inhibition of hERG-chaperone complexes and increases calcium currents by a faster cellular process. We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As(2)O(3). Our results suggest that calcium-channel antagonists will be useful in normalizing QT prolongation during As(2)O(3) therapy. As(2)O(3) is the first example of a drug that produces hERG liability by inhibition of ion-channel trafficking. Other drugs that interfere with proteins in the processing pathway of cardiac ion channels may be proarrhythmic for similar reasons.     

The mode of vasorelaxing action of melatonin in rabbit aorta.

1. The vasorelaxing effect of melatonin on the contractile response to 5-hydroxytryptamine (5-HT) was investigated in rabbit isolated aorta. 2. Melatonin (10(-5)-10(-3) M) caused relaxation of the 5-HT (10 M) response in a concentration-dependent manner. Nifedipine (10(-6) M) did not affect the relaxing action of melatonin. 3. Pretreatment with methylene blue (10(-5) M) or nitroglycerin (3 x 10(-8) M) inhibited or potentiated, respectively, the relaxing action of melatonin. 4. Pretreatment with melatonin (10(-3) M) or M&B 22.948 (10(-3) M) potentiated the relaxing effect of nitroglycerin (10(-9)-10(-5) M) on the contraction induced by PGF2 alpha (4 x 10(-6) M). The effect of a combined treatment with melatonin and M&B 22.948 was not significantly different from that of a single treatment with M&B 22.948. 5. Melatonin (10(-5)-10(-3) M) inhibited the activity of cGMP-phosphodiesterase, in a concentration-dependent manner. 6. These results suggest that the vasorelaxing action of melatonin may be due to an increase in the level of cGMP.     

Characterization of benzodiazepinooxazoles: crystal and molecular structure of trans and cis isomers of oxazolam.

The stereochemistry of the trans and cis isomers of 2(S)- and 2(R)-oxazolam is described. A total of four molecular structures of the 11b(R) and 11b(S) diastereomers of 2(S)- and 2(R)-oxazolam have been revealed by X-ray diffraction techniques. 2(S)-Oxazolam crystallizes in space group P2(1)/c, with cell dimensions a = 16.180(2) A, b = 8.791(2) A, c = 13.574(2) A, and beta = 102.07(1) degrees. The molecule in an asymmetric unit exhibited disorder at the 2-carbon (C2) atom, and the structures for trans and cis isomers have been resolved crystallographically. 2(S)-Oxazolam forms polymeric chains with intermediation of ethanol through hydrogen bonding. 2(R)-Oxazolam crystallizes in space group P1, with cell dimensions a = 7.754(1) A, b = 8.654(1) A, c = 15.795(2) A, alpha = 104.09(1) degrees, beta = 91.19(1) degrees, and gamma = 114.00(1) degrees. A similar disorder at the C2 position has been elucidated by a mixture of trans- and cis-2(R)-oxazolams. The two 2(R)-oxazolam molecules form a dimer with a hydrogen bond net. The structural details, focusing on the conformation and molecular complex formation of both oxazolams, have been discussed in connection with the oxazolidine ring stability and the crystal polymorph.     

Kinetic study of the reaction of cisplatin with thiols.

The reactions of cisplatin [cis-diamminedichloroplatinum(II), CDDP] with glutathione (GSH) and drug thiols were investigated at 37 degrees C in 100 mM Tris-NO(3), pH approximately 7.4, using a clinically relevant concentration of CDDP (33 micro M), a large excess of GSH (16.5 mM), and [NaCl] of 4.62 mM. The conditions were designed to mimic passage of CDDP through the cytosol. The reactions were studied by UV-absorption spectroscopy, high-pressure liquid chromatography (HPLC), and atomic absorption spectroscopy. The initial rates, detected by UV absorbance, confirmed that the reactions are first order in [CDDP]. The HPLC peak corresponding to CDDP was analyzed for platinum content by atomic absorption spectroscopy, which decreased exponentially with time, confirming that the reactions are first order in [CDDP] and allowing determination of the pseudo first order rate constants (k(1)). For reaction of the dichloro form of CDDP with GSH, the k(1) value was approximately 2.2 x 10(-4) s(-1) (t(1/2) of approximately 53 min), giving the second order rate constant value (k(2)) of approximately 1.3 x 10(-2) M(-)1 s(-1). Reaction of a mixture of the aquated forms of CDDP with GSH gave a lower k(1) value ( approximately 0.9 x 10(-4) s(-1)). Reaction of CDDP with sodium 2-mercaptoethanesulfonate (mesna) gave a k(1) value of approximately 1.8 x 10(-4) s(-1) (t(1/2) of approximately 65 min and k(2) of approximately 1.1 x 10(-2) M(-1) s(-1)). Reaction of CDDP with S-2-(3-aminopropylamino)ethanethiol (WR-1065) gave a k(1) value of approximately 12.0 x 10(-4) s(-1) (t(1/2) of approximately 10 min and k(2) of approximately 7.3 x 10(-2) M(-)1 s(-1)). The relatively slow reaction rate of CDDP with GSH is consistent with the efficient DNA platination by CDDP in the presence of millimolar concentration of GSH in the cytosol.     

Variations of the digestive absorption kinetics of carbaryl with the nature of the vehicle

Blood kinetics of 1-naphthyl-N-methyl[14C] carbamate were determined after intravenous injection in DMSO, and after intragastric and intraduodenal administration in DMSO, oil, gum tragacanth and milk. The acetylcholinesterase inhibition and the level of 14C-activity were both determined in the blood over various periods of time. The values of the absorption rate constants after intragastric and intraduodenal administration were found to be: 0.5 h(-1) and 7 h(-1) with DMSO, 0.6 h(-1) and 0.42 h(-1) with oil, 0.13 h(-1) and 0.22 h (-1) with gum tragacanth and 0.10 h(-1) with milk. Appearance of the toxic effect (the inhibition of the acetylcholinesterases) was closely related to the absorption rate constants which themselves depend on the administration vehicle employed.     

Agonist-antagonist actions and stereoselectivity of optical pairs of some N-substituted alpha-N-normetazocines

alpha-(-)-, (+)-, and (+/-)-N-4-Methylpentyl-, (-)- and (+)-N-cis-3-chloroallyl-, and (-)- and (+)-N-propynyl-N-normetazocine (I, II, and III, respectively) have been prepared from alpha-(-)-, (+)-, and (+/-)-N-normetazocine (IV) and tested for antinociceptive activity in mice and in morphine-dependent rhesus monkeys. The results obtained with Ia and b somewhat resemble the results obtained with the corresponding phenazocine isomers, whereas those observed with IIa and b more nearly correspond with those reported for (+)- and (-)-N-allyl-N-normetazocine (SKF 10,047; NANM). The propynyl isomers (IIIa and b) display profiles of activity more closely like the corresponding isomers of metazocine. Evidence is considered which suggests that some of the (+)-isomers merit closer scrutiny in animal and human studies.     

Properties of the reaction of chromate with metallothionein

The reactivity of chromate or Cr(VI) with rabbit liver metallothionein (MT) was explored in this study. Zn(7)-MT reacts very slowly with Cr(VI) in a process characterized by a second-order rate constant of 3.9 x 10(-)(4) M(-)(1) s(-)(1). During the reaction, Zn(2+) was released from the protein. In contrast, apo-MT reduces chromate quicker and in this reaction is much more effective as a reducing agent, when compared to Cys or GSH. The kinetics are consistent with a reaction pathway involving an initial binding step followed by the reduction of Cr(VI). In the process, MT sulfhydryl groups were oxidized at the same rate that Cr(VI) disappeared. A Cr(V) intermediate was detected by EPR spectroscopy immediately upon mixing apo-MT with Cr(VI). The Cr(V) signal decayed during the reaction but was quite stable and could be observed for hours once the supply of thiols was depleted. The g values for the Cr(V) species were 2.014 and 1.987. The kinetics of the reaction of Cr(VI) and the concentration of the intermediate Cr(V) signal were independent of the oxygen concentration and were unaffected by the presence of superoxide dismutase, catalase, or DMSO. In the presence of oxygen, oxy radicals were generated according to ESR spin-trapping experiments with 5,5'-dimethyl-1-pyrroline-N-oxide. Superoxide dismutase decreased and catalase or DMSO largely inhibited the formation of the spin-trapped adduct. Cr(III), the presumed final species of the Cr(VI) reduction, formed a stable complex with apo-MT in the absence of oxygen with an average stoichiometry of two Cr ions bound per protein molecule. Upon addition of O(2), the complex slowly dissociated.     

苯磺酸贝他斯汀的不对称合成

用（S）-[Ru（BINAP）Cl2]2（NEt3）作催化剂，不对称氢化还原（4-氯苯基）-（吡啶-2-基）-甲酮得到（S）-（＋）-（4-氯苯基）-（吡啶-2-基）-甲醇，与4-（4-溴哌啶-1-基）丁酸乙酯缩合，再经水解、成盐得到抗过敏药苯磺酸贝他斯汀，总收率57%。     

Doxorubicin-dependent reduction of ferrylmyoglobin and inhibition of lipid peroxidation: implications for cardiotoxicity of anticancer anthracyclines

Lipid peroxidation has been proposed to mediate cardiotoxicity induced by doxorubicin (DOX) and other anticancer anthracyclines; however, there have been reports showing that DOX can also inhibit lipid peroxidation. Here we characterized the effects of DOX on the oxo-ferryl moiety [Fe(IV)=O, Mb(IV)] of H(2)O(2)-activated myoglobin, a lipid oxidant likely formed in the heart during treatment with DOX. Mb(IV) was formed in vitro by reacting 100 microM H(2)O(2) with 50 microM horse heart metmyoglobin (Mb(III)). Spectral studies showed that DOX reduced Mb(IV) to Mb(III), half-maximal regeneration of Mb(III) occurring at approximately 18 microM DOX. Comparisons between DOX, its aglycone doxorubicinone, and other approved or investigational anthracyclines or model compounds (daunorubicin, idarubicin, aclarubicin, and naphthazarin), showed that DOX reduced Mb(IV) through the hydroquinone moiety of its tetracyclic ring. DOX inhibited Mb(IV)-dependent peroxidation of arachidonic acid, suppressing the formation of thiobarbituric acid-reactive substances with an IC(50) of approximately 18 microM. Lipid peroxidation was inhibited also by the hydroquinone-containing daunorubicin and idarubicin but not by the hydroquinone-deficient aclarubicin; moreover, neither simple hydroquinone nor other known Mb(IV) reductants (ascorbate, glutathione, and ergothioneine) reached measurable IC(50)s in a micromolar range. DOX-dependent inhibition of lipid peroxidation correlated with its ability to reduce Mb(IV) to Mb(III) in competition with arachidonic acid (r = 0.83, P = 0.029); it did not correlate with its ability to scavenge other free radical species [like e.g., peroxyl radicals generated through the thermal decomposition of 2,2'-azo-bis(2-amidinopropane)]. DOX reduced Mb(IV) and inhibited lipid peroxidation also when H(2)O(2), Mb(III) and arachidonic acid were reacted in cytosol of human myocardial biopsies, a model developed to predict the cardiotoxic mode of action of DOX in patients. These results illustrate "antioxidant" properties of DOX, mediated by reduction of Mb(IV) to Mb(III), and cast doubts on lipid peroxidation as a causative mechanism of anthracycline-induced cardiotoxicity.