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R F Novak

Publications and source records attributed to R F Novak.

At least 73 records · Page 4Linked to original sources
PubMed1991

Pyridine effects on P450IIE1, IIB and IVB expression in rabbit liver: characterization of high- and low-affinity pyridine N-oxygenases.

The effects of pyridine exposure on expression of cytochromes P450IIE1, IIB and IVB in rabbit hepatic microsomes and their respective role in pyridine N-oxide production has been examined. Immunoblot analysis revealed that pyridine administration caused a substantial increase in P450IIE1 levels, failed to affect P450IIB content and marginally increased the expression of P450IVB. In an effort to implicate specific forms of P450 in pyridine N-oxide production, the kinetics of pyridine N-oxide formation in uninduced and induced rabbit hepatic microsomal preparations were obtained. Pyridine-induced microsomes exhibited a single low Km value of 81 microM with a approximately 2.5-fold increase in Vmax (2.44 nmol/min/mg protein) relative to uninduced microsomes. Interestingly, pyridine N-oxide production in phenobarbital-induced microsomes were also monophasic, exhibiting a single, high Km value of 949 microM and a Vmax of 3.3 nmol/min/mg protein, a approximately 10-fold increase over the uninduced preparations. In contrast, uninduced and isosafrole-induced rabbit hepatic microsomes both exhibited biphasic kinetics; uninduced microsomes gave Km values of 85 and 973 microM, whereas isosafrole-induced microsomes yielded Km values of 229 and 1733 microM, respectively, with a Vmax somewhat less than uninduced microsomes. When kinetic data were normalized for P450 content, a pronounced substrate specificity was detected for both pyridine- and phenobarbital-induced microsomes. para-Nitrophenol hydroxylase activity was enhanced approximately 6-fold in pyridine-induced microsomes consistent with elevated levels of P450IIE1. para-Nitrophenol competitively inhibited (Ki = 13 microM) the production of pyridine N-oxide in pyridine-induced microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A brief review of the anatomy, histology, and ultrastructure of the full-term placenta.

A brief review of the morphologic features of the term placenta is presented using schematic drawings and light and transmission electron microscopic illustrations of individual features. Some areas of current and past controversy are identified regarding placental structure. The review is intended to be an introduction for those examining placentas in surgical pathology laboratories.

Basement Membrane↗
PubMed1990

Evidence for increased translational efficiency in the induction of P450IIE1 by solvents: analysis of P450IIE1 mRNA polyribosomal distribution.

The potential for enhanced translational processing of P450IIE1 mRNA during the early phase of P450IIE1 induction by pyridine or acetone was assessed by hybridization analysis of polyribosomal P450IIE1 mRNA distribution in rat hepatic tissue. Optical absorbance profiles of polyribosomal fractions exhibited an apparent shift at 5 h following pyridine administration relative to control. Slot and Northern blot analyses for P450IIE1 mRNA in the cytoplasmic extracts isolated from 5 h pyridine-treated rats demonstrated a shift in distribution of P450IIE1 message toward heavier polyribosomal fractions and Northern blot analysis suggested the presence of different populations of P450IIE1 mRNA. Slot blot analyses also demonstrated a shift in the polyribosomal distribution of P450IIE1 mRNA at 12 h following pyridine treatment; in contrast, hybridization analysis for P450IA1 revealed no shift in polyribosomal distribution of P450IA1 mRNA. Acute acetone administration to animals also resulted in a similar shift in polyribosomal distribution of P450IIE1 mRNA as compared to control. These data suggest that P450IIE1 mRNA shifts toward larger polyribosomes following acute exposure of animals to pyridine or acetone and provide evidence that induction of P450IIE1 at early times following acute pyridine or acetone administration involves enhanced translational efficiency through increased loading of ribosomes on P450IIE1 mRNA.

Acetone↗
PubMed1990

Role of P450IIE1 in the metabolism of 3-hydroxypyridine, a constituent of tobacco smoke: redox cycling and DNA strand scission by the metabolite 2,5-dihydroxypyridine.

The metabolism of 3-hydroxypyridine, a significant constituent of tobacco smoke, to 2,5-dihydroxypyridine has been characterized in hepatic microsomes and in the reconstituted enzyme system using purified forms of P450. The redox cycling activity of the metabolite and its ability to damage DNA in vitro have been examined. Pyridine-induced microsomes, which contain elevated levels of P450IIE1 (Kim et al., J. Pharmacol. Exp. Ther., 246: 1175-1182, 1988), catalyzed an 8-fold increase in the production of 2,5-dihydroxypyridine, relative to control, which showed biphasic kinetics. Pyridine-induced rabbit hepatic microsomes exhibited a Vmax of 5.9 nmol 2,5-dihydroxypyridine/min/mg protein and a Km value of 110 microM. In contrast, phenobarbital- and isosafrole-induced microsomes had Vmax values of 2.5 and 1.2 nmol/min/mg protein and Km values of 590 and 134 microM, respectively. Pyridine-induced rat hepatic microsomes also exhibited elevated catalytic activity toward the hydroxylation of 3-hydroxypyridine, with an 8-fold increase in Vmax (2.74 nmol/min/mg protein) relative to uninduced rat hepatic microsomes (Vmax = 0.34 nmol/min/mg protein). In the reconstituted system, cytochrome P450IIE1 displayed the greatest activity in the production of 2,5-dihydroxypyridine of the major forms of rabbit P450 examined. P450IIE1 was 34-fold more active than P450IIB1 and 12-fold more active than P450IA2 in the production of 2,5-dihydroxypyridine. The redox cycling activity of 2,5-dihydroxypyridine has been characterized. The rate of NADPH oxidation in the presence of 0.5 mM 2,5-dihydroxypyridine was stimulated approximately 4-fold (69.2 nmol NADPH oxidized/min/mg protein), relative to control (16 nmol/min/mg protein). 2,5-Dihydroxypyridine at 0.5 and 1.0 mM produced a 12- and 17-fold increase, respectively, in the rate of superoxide anion production compared to control, as monitored by the SOD-inhibitable reduction of acetylated cytochrome c. 3-Hydroxypyridine alone failed to increase the rate of superoxide production. Inclusion of reduced glutathione in the incubation resulted in a pronounced decrease in the 2,5-dihydroxypyridine-stimulated rate of cofactor oxidation and superoxide production. The ability of 2,5-dihydroxypyridine to damage DNA was assessed by monitoring phi X-174 DNA strand scission. The band intensity of the supercoiled form of DNA, when incubated with 1 mM 2,5-dihydroxypyridine, decreased substantially, with a concomitant increase in intensity of the band associated with the open circular form of DNA. The change in phi X-174 DNA topology produced by 2,5-dihydroxypyridine was accelerated in a dose-dependent manner, with an estimated EC50 of approximately 60 microM.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Induction of rat hepatic P450IIE1 (CYP 2E1) by pyridine: evidence for a role of protein synthesis in the absence of transcriptional activation.

The dose- and time-dependent induction of P45OIIE1 in rat liver by pyridine has been characterized. A single injection of pyridine (100 mg/kg, i.p.) increased P450IIE1 levels 2-, 3- and 4-fold at 6, 10 and 24 hr, respectively, relative to controls as evidenced by metabolic activity and Western blot analysis. Induction of IIE1 was dose-dependent over the range 10 to 200 mg/kg. Cycloheximide administration completely prevented the induction of P450IIE1 by pyridine, whereas actinomycin D administration had no appreciable effect. Pyridine induction of IIE1 did not occur by transcriptional activation. Hybridization analysis failed to reveal an increase in IIE1 message in either total RNA or poly(A+) mRNA following pyridine treatment, although a slight decrease in poly(A+) mRNA was noted. The rate of P450IIE1 synthesis was assessed by labelling of proteins with [14C]leucine in vivo, followed by autoradiographic analysis. Increased intensity of a protein band comigrating with purified IIE1 was observed in microsomes isolated from rats at 5 hr following either pyridine or acetone treatment, as compared to controls. An increase in intensity was also noted for protein bands migrating in the region of 62 and 50 kDa. These results suggest that induction of P450IIE1 at early times following acute pyridine exposure involves protein synthesis possibly through increased translational efficiency.

Animals↗
PubMed1988

Characterization of hydrazine-stimulated proteolysis in human erythrocytes.

The ability of hydrazine, acetylphenylhydrazine, methylhydrazine, and phenylhydrazine to stimulate proteolysis in red cells has been characterized. All four hydrazines effectively stimulated proteolysis in red cells and in hemolysate as evidenced by a two- to threefold increase in the rate of tyrosine release. The rate of tyrosine release varied linearly with time, increased with increasing concentration of hydrazine, and also increased as a function of hematocrit. The rank order for stimulation of proteolysis in red cells was phenylhydrazine greater than methylhydrazine greater than hydrazine approximately equal to acetylphenylhydrazine. Inhibitors of glycolysis in red cells only minimally (13-27%) decreased the rate of tyrosine release stimulated by the different hydrazines. Agents which diminished electron transport decreased the rate of tyrosine release. NADP inhibited the rate of tyrosine release stimulated by hydrazine, methylhydrazine, and acetylphenylhydrazine by approximately 36 to 41%; 2'-AMP was less effective. The rate of tyrosine release resulting from insult by the hydrazines was increased slightly by methylene blue, moderately inhibited (approximately 10 to 27%) by the chelator o-phenanthroline and inhibited approximately 30 to 40% by N-ethylmaleimide. Use of an oxygen-depleted atmosphere (N2) increased slightly the rate of tyrosine release stimulated by the hydrazines; in contrast, carbon monoxide decreased proteolysis stimulated by hydrazine, methylhydrazine, and acetylphenylhydrazine by approximately 50%. Although the antioxidants dimethylfuran, dimethylthiourea, and methylsulfoxide failed to diminish proteolysis stimulated by the hydrazines, N-acetylcysteine exerted a protective effect, decreasing hydrazine-stimulated tyrosine release in red cells approximately 30 to 50%. Inclusion of 3-amino-1,2,4-triazole in the incubation failed to increase further the rate of hydrazine-stimulated proteolysis. These data suggest that more reactive free radicals generated from the hydrazine are responsible for protein damage, that damaged protein (hemoglobin) is degraded via proteolysis, and that an ATP-independent process primarily participates in the degradation of abnormal proteins in the red cell. Thus, proteolytic enzymes present in the erythrocyte appear to exert a protective effect against cellular damage through the removal of abnormal proteins generated as a consequence of xenobiotic insult. The ability of proteolytic enzymes to recognize and degrade abnormal proteins may be of importance in using protein (hemoglobin)-xenobiotic adducts to assess exposure to toxic agents (risk assessment).

Adenosine Triphosphate↗
PubMed1988

Nitrofurantoin-stimulated proteolysis in human erythrocytes: a novel index of toxic insult by nitroaromatics.

Nitrofurantoin is an antimicrobial agent that causes nonimmune hemolytic anemia in susceptible populations and produces oxidant stress and cellular damage by mechanisms that differ from those associated with oxidants such as phenylhydrazine, which has been shown to stimulate proteolysis in red cells (Goldberg and Boches, 1982). Thus a study of the effects of nitrofurantoin on proteolysis in normal human red cells and red cell hemolysate has been conducted. Nitrofurantoin produced greater than a 3- and an approximately 5-fold increase in the rate of tyrosine release from red cells at 100 and 800 microM, respectively, compared with untreated red cells. In hemolysates nitrofurantoin also effectively increased proteolysis with a 2.4- and 4.0-fold increase in the rate of tyrosine release monitored at 100 and 800 microM, respectively, relative to controls. Stimulation of proteolysis by nitrofurantoin occurred linearly with time and with hematocrit over the range 5-25%. The rate of nitrofurantoin-stimulated proteolysis varied with glucose concentration in the incubation medium with a 2-fold increase in activity monitored between 2 and 10 mM glucose. Inhibitors of flavoprotein activity (electron transport), such as 2'-AMP and NADP, decreased nitrofurantoin-enhanced proteolysis in red cells to control levels, whereas methylene blue provided only a slight increase in proteolysis and an anaerobic environment (N2) stimulated significantly the rate of tyrosine production. Although N-acetylcysteine protected against the stimulation of proteolysis produced by 10 microM nitrofurantoin, this protective effect was diminished at higher concentrations of drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1988

Pyridine induction of cytochrome P-450 in the rat: role of P-450j (alcohol-inducible form) in pyridine N-oxidation.

Previous research has shown that pyridine (PY) pretreatment of rabbits elevates total hepatic microsomal cytochrome P-450 content in association with the appearance of intense bands in the region of P-450LM4 and LM3 in the electrophoretic pattern of the microsomes and increased rates of PY N-oxide production and N-nitrosodimethylamine, alcohol and aniline metabolism. In the present study, PY administration (100 mg/kg i.p., 4 days) to rats was found to elevate hepatic microsomal cytochrome P-450 content approximately 2.5-fold as compared to controls. Sodium dodecylsulfate-polyacrylamide gel electrophoresis revealed a protein band of enhanced intensity migrating in the region of P-450j, the major ethanol-inducible form of rat liver cytochrome P-450. Immunochemical analysis confirmed that the level of immunoreactive P-450j protein was increased in PY-induced microsomes as compared to preparations from control, phenobarbital- or beta-naphthoflavone-induced animals. The rate of PY N-oxide production was enhanced 4-fold in PY-induced microsomes relative to untreated controls and was approximately 1.5- to 2-fold greater than that monitored for either phenobarbital- or beta-naphthoflavone-induced microsomes. When data were normalized for increased P-450 content, an altered substrate specificity was suggested for the PY-induced microsomes. para-Nitrophenol hydroxylase activity, which is exhibited primarily by the ethanol-inducible form of P-450, was elevated approximately 4-fold in PY-induced microsomes relative to uninduced microsomes and, when expressed per nanomol of P-450, was approximately 2- to 3-fold greater in PY-induced preparations as compared to phenobarbital-, beta-naphthoflavone-induced, or uninduced microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Hydroxylase↗
PubMed1987

Anthracenedione antineoplastic agent effects on drug metabolism in vitro and in vivo: relationship between structure and mechanism of inhibition.

Two anthracenedione antineoplastic agents, mitoxantrone and the nonhydroxylated analog, ametantrone, were found to inhibit hepatic microsomal cytochrome P-450-dependent drug metabolism in vitro and in vivo. Ethoxycoumarin deethylase activity of phenobarbital-induced rabbit hepatic microsomes was inhibited 56 and 100% at 0.1 and 0.5 mM mitoxantrone, respectively, whereas activity was inhibited 38 and 88% at 0.1 and 0.5 mM ametantrone, respectively. Both mitoxantrone and ametantrone were noncompetitive inhibitors of ethoxycoumarin metabolism. Aryl hydrocarbon hydroxylase activity of hepatic microsomes was diminished 41 and 56% by 1 and 3 mM mitoxantrone, respectively; identical concentrations of ametantrone inhibited metabolism by 20 and 31%, respectively. In contrast to the inhibitory influence of both agents on monooxygenase activity, a differential effect on NADPH oxidation was observed. In the presence of benzo[alpha]-pyrene, mitoxantrone enhanced microsomal NADPH oxidation by 21%, whereas ametantrone produced a 22% decrease in cofactor oxidation relative to the control rate. The anthracenediones also inhibited hepatic cytochrome P-450-dependent monooxygenase activity in vivo, as evidenced by altered hexobarbital sleep times of mice. Mitoxantrone (20 and 40 mg/kg) prolonged sleep time by 59 and 68%, respectively; ametantrone (50 mg/kg) produced a 56% enhancement. These results demonstrate that both mitoxantrone and ametantrone inhibit drug metabolism in vitro and in vivo.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1987

Silica and glomerulonephritis: case report and review of the literature.

A 54-year-old foundry worker with extensive silica exposure, but no pulmonary disease, developed the nephrotic syndrome and renal failure over a 3-month period. Renal biopsy demonstrated a proliferative glomerulonephritis; energy dispersive x-ray analysis detected silicon within the renal tubules. Measurements of respirable silica at the foundry revealed levels up to 2.5 times the current occupational standard. Similar glomerular disease has been reported in silica-exposed animals and workers with silicosis. This case suggests that clinicians should include silica exposure in the differential diagnosis of unexplained diffuse proliferative glomerulonephritis, renal disease may occur without clinically evident pulmonary disease in silica exposure, and silica-induced glomerulonephritis warrants further clinical and epidemiologic research.

Glomerulonephritis↗
PubMed1987

Inhibition and induction of rabbit liver microsomal cytochrome P-450 by pyridine.

The effects of acute and chronic administration of pyridine (PY) on rabbit hepatic microsomal cytochrome P-450-catalyzed drug metabolism have been examined. PY inhibited cytochrome P-450-catalyzed drug metabolism in vitro and in vivo. Noncompetitive inhibition of microsomal drug metabolism was observed with inhibitory constant (Ki) values ranging between 2.0 and 6.0 mM. Acute PY administration, 100 mg/kg i.p., prolonged hexobarbital sleep time in rats 2.5-fold. Chronic administration of PY to rabbits resulted in increased hepatic microsomal cytochrome P-450 content, with induction of different form(s) exhibiting elevated catalytic activities toward PY, N-nitrosodimethylamine, alcohols and aniline. PY administration (100 mg/kg i.p. for 5 days) to rabbits increased hepatic microsomal cytochrome P-450 content over 2-fold relative to uninduced animals. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of PY-induced microsomes revealed protein bands of enhanced intensity occurring in the regions of P-450 LM3 and LM4. Both PY- and imidazole-induced microsomes were effective in the production of PY N-oxide, with Vmax values of 1.6 and 1.8 nmol/min/mg of protein, respectively. When rates were normalized for P-450 content, PY- and imidazole-induced microsomes produced 0.9 nmol of PY N-oxide/min/nmol of P-450, comparable to that obtained for PB-induced suspensions. N-nitrosodimethylamine N-demethylase activity was enhanced 2.5- and 6-fold relative to PB- and beta-naphthoflavone-induced microsomes, respectively. A single low KM value of 0.17 mM was obtained for N-nitrosodimethylamine N-demethylase activity in PY-induced microsomes; in contrast PB- and beta-naphthoflavone-induced microsomes yielded biphasic kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of anthrapyrazole antineoplastic agents on lipid peroxidation.

The effects of three anthrapyrazoles and an aminoacridine derivative on doxorubicin- and iron-stimulated lipid peroxidation in rabbit hepatic microsomes have been characterized. Two anthrapyrazoles, CI-937 and CI-942, were potent inhibitors of lipid peroxidation with 15 microM drug inhibiting the rate of peroxidation 70 to 90%. In contrast CI-941 was relatively ineffective in inhibiting lipid peroxidation with only 35% inhibition occurring at 100 microM drug. CI-921, an aminoacridine derivative, diminished lipid peroxidation by 65% at 15 microM. All four drugs failed to decrease the rate of doxorubicin-stimulated NADPH oxidation at concentrations less than 50 microM, suggesting that inhibition of lipid peroxidation was not the result of diminished enzyme activity. CI-937 formed a 2:1 complex with ferric ion, KD = 47 microM, which was reversible with EDTA.

Amsacrine↗
PubMed1986

Inhibition of angiogenesis by the antineoplastic agents mitoxantrone and bisantrene.

The effects of mitoxantrone and bisantrene on angiogenic responses induced by tumor cell-conditioned media in the avascular cornea of rat eye have been evaluated. Both mitoxantrone and bisantrene effectively inhibited, in a concentration-dependent manner, angiogenesis induced by conditioned media obtained from either a hamster buccal pouch carcinoma cell line or P388D1 murine macrophage-like cells. Whereas vessel ingrowth in corneas containing tumor cell-conditioned media was detected as early as day 2 or 3 and was maximal by day 7, inclusion of mitoxantrone or bisantrene in the conditioned media at a 1:1 ratio (160 microM mitoxantrone or 32 microM bisantrene) resulted in complete inhibition of angiogenesis throughout the 14-day evaluation period. When concentrations of 64 and 32 microM mitoxantrone or 13 and 6.4 microM bisantrene were employed there was a marked delay in the appearance of capillary blood vessels (day 5 to 7) and a reduction in the intensity of angiogenic responses. No untoward toxicity to the tissue was observed at the concentrations of mitoxantrone or bisantrene employed.

Animals↗
PubMed1985

Mitoxantrone and ametantrone inhibit hydroperoxide-dependent initiation and propagation reactions in fatty acid peroxidation.

The anthracenedione antineoplastic agents mitoxantrone and ametantrone are potent inhibitors of basal and drug-stimulated lipid peroxidation in a variety of subcellular systems (Kharasch, E. D., and Novak, R. F. (1983) J. Pharmacol. Exp. Ther. 226, 500-506). The mechanism by which these compounds function as antioxidants has been investigated using enzymic and chemical systems. Mitoxantrone and ametantrone inhibited NADPH-cytochrome P-450 reductase- and xanthine oxidase-catalyzed conjugated diene formation from linoleic acid in a concentration-dependent manner with half-maximal inhibition achieved at approximately 0.5 microM anthracenedione. Inhibition of linoleic acid peroxidation was not attributable to a decrease in P-450 reductase activity, hydroxyl radical scavenging, or iron chelation by the anthracenediones. Nonenzymic fatty acid peroxidation was also inhibited by the anthracenediones. Linoleic acid oxidation initiated by superoxide (ferrous iron autoxidation) or by hydroxyl radicals (Fenton's reagent) was diminished by mitoxantrone and ametantrone after a brief delay, suggesting an effect subsequent to activated oxygen-dependent initiation. In contrast, linoleic acid oxidation initiated by iron-dependent hydroperoxide decomposition was inhibited immediately. Reinitiation of linoleic acid oxidation in an anthracenedione-inhibited system was accomplished only by superoxide generation, but not by fatty acid hydroperoxide decomposition. These results suggest the anthracenediones diminished neither oxygen radical formation nor oxygen radical-dependent initiation of peroxidation. Rather, inhibition of fatty acid peroxidation by mitoxantrone and ametantrone results from the inhibition of hydroperoxide-dependent initiation and propagation reactions.

Anthraquinones↗
PubMed1985

Metabolic and morphologic effects of the antimicrobial agent nitrofurantoin on human erythrocytes in vitro.

We have reported previously that the antimicrobial nitrofurantoin stimulates superoxide production and methemoglobin formation from HbO2 as an isolated hemeprotein and in hemolysates [M. Dershwitz and R. F. Novak, J. biol. Chem. 257, 75 (1982); M. Dershwitz and R. F. Novak, J. Pharmac. exp. Ther. 222, 430 (1982)]. The production of hydrogen peroxide and methemoglobin by nitrofurantoin has been determined in normal erythrocytes in vitro. Hydrogen peroxide production increased 5-fold during a 20-hr incubation in the presence of 840 microM nitrofurantoin, while methemoglobin content increased to over 20% of the total hemoglobin concentration of the cells. Consequent metabolic and morphologic alterations also occurred. Concomitant with nitrofurantoin-stimulated hydrogen peroxide production were time- and concentration-dependent decreases in cellular levels of GSH and ATP, as well as alterations in red cell morphology. Significant differences in GSH and ATP levels between control and nitrofurantoin-treated erythrocytes occurred after 12 hr and proceeded maximally from 18 to 21 hr. After a 21-hr incubation, 840 microM nitrofurantoin caused the cellular GSH and ATP levels to fall 65 and 75%, respectively, while controls exhibited only 29 and 43% decreases in ATP and GSH levels, respectively. Studies on the concentration dependence of such decreases demonstrated that the EC50 values for depletion of GSH and ATP were similar in blood obtained from an individual donor. The EC50 values varied from approximately 10 microM to 100 microM among the various donors whose blood was studied. Incubation of normal red cells with nitrofurantoin also resulted in an increased conversion of red cells to echinocytes as observed by scanning electron microscopy. These metabolic effects, coupled with increased oxidative stress via hydrogen peroxide generation, lend support to the mechanism for nitrofurantoin-induced hemolysis in erythrocytes compromised by certain enzyme deficiencies which result in low basal levels of GSH or diminished rates of GSH synthesis.

Adenosine Triphosphate↗
PubMed1985

Mitoxantrone: propensity for free radical formation and lipid peroxidation--implications for cardiotoxicity.

Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone; dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofactor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100 microM MXN or AM was only 15% and 2% respectively of that produced by 100 microM anthracycline. The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50 microM inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2- and 2.5-fold at 100 and 200 microM, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 microM anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 microM MXN and AM, whereas 50 microM DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4 microM (MXN) and 6 microM (AM). Moreover, both MXN and AM potently inhibited iron (100 microM)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 microM anthracenedione.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗