- Email: [email protected]
Magnesium lithospermate B ameliorates cisplatin-induced injury in cultured renal epithelial cells
Exp Toxic Patho11997; 49: 343-346 Gustav Fischer Verlag
'Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan 2Faculty of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan
Magnesium lithospermate B ameliorates cisplatin-induced injury in cultured renal epithelial cells TAKAKO YOKOZAWA', ERBO DONG', HIKOKICHI OURA', GEN-ICHIRO NONAKA 2 , and ITSUO NISHIOKA 2 With 3 figures Received: March 30, 1996; Revised: June 26, 1996; Accepted: July 11, 1996 Address for correspondence: Dr. TAKAKO YOKOZAWA, Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0 I , Japan. Key words: Magnesium lithospermate B; Cisplatin; Renal injury; Malondialdehyde; Lactate dehydrogenase; LLC-PK,.
Summary A study was conducted to clarify whether magnesium Iithospermate B ameliorates cisplatin-induced renal injury in terms of lactate dehydrogenase and malondialdehyde leakage from LLC-PK, cells in culture. Magnesium lithospermate B was shown to suppress the cytotoxicity of cisplatin, the suppressive effect increasing with the dose of magnesium lithospermate B.
In the present study using cultured cells, we investigated whether or not magnesium lithospermate B, which is known to ameliorate through the reduction of uremic toxins such as urea nitrogen, creatinine, methyl guanidine and guanidinosuccinic acid in adenine-induced renal failure rats, an animal model of renal tubular impairment (YOKOZA w A et al. 1991 a, 1991 b, I 992a, 1992b, 1993a, 1993b), is also effective against cisplatin-induced renal injury.
Introduction Material and methods cis-Diamminedichloroplatinum (cisplatin) is a platinum chelate having high antitumor activity against carcinomas of the testis, ovary, urinary bladder, prostate, head and neck. However, it has adverse side effects on the kidney, bone marrow and digestive organs. In particular, the risk of renal injury limits the use of this drug in a clinical setting (BLACHLEY and HILL 1981; GOLDSTEIN and MAYOR 1983; WEINER and JACOBS 1983; LITTERST 1984). To enhance the therapeutic antitumor effect of cisplatin while suppressing its injurious effect on the kidney , its combined use with other drugs such as diuretics and the development of harmless cisplatin derivatives have been attempted by many researchers (GEMBA 1991). On the other hand, in various fields including nephrology efforts have been made to establish in vitro experimental systems which do not require complete in vivo animal models. GEMBA and FUKUISHI (1991), using cultured renal tubular cells, have demonstrated that lactate dehydrogenase (LDH) leaks into the culture medium in the presence of cisplatin, and that the cells are damaged at concentrations of cisplatin close to its therapeutic level in blood.
Medium and reagents: Dulbecco's modified Eagle medium/nutrient mixture F-12 (D-MEM/F-12) and fetal calf serum (FCS) were purchased from Life Technologies, Inc. (Grand Island, NY, USA) and Cell Culture Laboratories (Cleveland, OH, USA), respectively. Cisplatin was obtained from Sigma Chemical Co. (St. Louis, MO, USA). LDH and malondialdehyde (MDA) leakage assay: LLCPK, cells were maintained at 37 °C in a humidified atmosphere of 5 % CO 2 in air in 96-well culture plates (Corning Glass Works, Corning, NY) with 5 % FCS-supplemented D-MEMIF-12 medium. After confluence had been reached, the cells were seeded in culture plates at 104 per well. Cisplatin and/or magnesium lithospermate B were added to the culture 2 h later, and the plates were incubated for 48 h. Leakage ofLDH into the culture medium was assayed as an index of cytotoxicity using a commercial kit from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). The extent of lipid peroxidation was estimated by measuring the concentration of MDA as described by YAGI (1976). Purification of magnesium lithospermate B from Salviae Miltiorrhizae Radix: As reported previously (TANAKA et al. 1989), commercially available Salviae Miltiorrhizae Exp Toxic Pathol49 (1997) 5
343
Radix (Salvia Miltiorrhiza BUNGE) (1.0 kg) produced in China was extracted twice with water (1.5 liters) at 80°C. After removal of insoluble matter by filtration, the filtrate was concentrated under reduced pressure (40°C) and subjected to MCI-gel CHP-20P (7.5 cm i.d. x 35 cm) column chromatography. After washing the column with water, elution with 50 % aqueous methanol yielded polyphenols (62 g), which were chromatographed using a Sephadex LH-20 column (5.0 cm i. d. x 42 cm) with water containing increasing amounts of ethanol to afford three fractions: I (4.8 g), II (0.35 g) and III (5.9 g), and compound 1 (7.56 g). Fractions I and III were rechromatographed separately on a Sephadex LH-20 column using water as an eluent to yield compound 2 (1.98 g) and a further fraction of compound 1 (4.3 g). Compound 1 was identified as magnesium lithospermate B on the basis of its \3C nuclear magnetic resonance spectrum, infrared spectrum, negative fast-atom bombardment mass spectrum, proton nuclear magnetic resonance spectrum, energy-dispersive X-ray analysis and other data. Its chemical structure is shown in fig. 1. Statistics: Results are presented as mean ± S. E. of 5 determinations. The data were analyzed for statistical signifi-
OH
cance using DUNNETI'S method. Differences at p < 0.05 were considered statistically significant.
Results As shown in fig. 2, LDH leakage from the cells into the culture medium increased after cisplatin had been added to the medium. Although there was no suppression of the cytotoxic effect of cisplatin in the presence of 2.5 11M magnesium lithospermate B, 12.5 11M suppressed the leakage significantly to 231.5 mID/m!. This suppression became more marked as the concentration of magnesium lithospermate B increased, the LDH activity (128.5 mID/ml) in the presence of 125 11M magnesium litho sperm ate B being comparable to that in the absence of cisplatin (116.6 mID/ml). When the effect of magnesium lithospermate B was examined in the absence of cisplatin, LDH leakage into the culture medium was found to be suppressed in a dose-dependent manner (fig. 2). Similar
OH OH
Fig. 1. Structural formula of magnesium lithospermate B.
300
~ ! .;:
..
250
200
~
t
150
til
==
100
~
50
Q
o Fig.2. Effect of cisplatin and magnesium lithospermate B (MLB) on LDH leakage from LLC-PK 1 cells. Statistical significance: #p < 0.001 vs. valuefor cisplatin only, *p < 0.01, **p < 0.001 vs. value for non-treatment. 344
Exp Toxic Pathol 49 (1997) 5
Fig. 3. Effect of cisplatin and magnesium lithospermate B (MLB) on MDA released from LLC-PK 1 cells. Statistical significance: #p < 0.001 vs. value for cisplatin only, *p < 0.05, **p < 0.01, ***p < 0.001 vs. value for non-treatment.
changes produced by magnesium lithospermate B were observed in the MDA values (fig. 3).
Discussion There is an urgent need to establish in vitro experimental systems which can replace in vivo animal models for analysis of drug actions and toxicity studies. Efforts in this direction have also been made in the field of nephrology. Among various established renal epithelial cell lines, hog-derived LLC-PK 1 cells are considered to be similar in character to the proximal uriniferous tubule, and MDCK cells to the distal uriniferous tubule and collecting tubule in the renal cortex (GASTRAUNTHALER 1988). Since it is known that cisplatin acts mainly on the straight part of the proximal uriniferous tubule, we used LLC-PK cells to . mvestigate the effect of magnesium lithospermate B on cisplatin-induced renal injury. The effect was determined in terms of the leakage of the lysosomal enzyme LDH from these cells into the culture medium through their damaged plasma membranes. It was found that the amount of LDH leakage from LLC-PK 1 cells was about 2A-fold greater in the presence of 0.25 11M cisplatin than in the absence of cisplatin, demonstrating the cytotoxicity of this drug. When magnesium lithospermate B was also present in the culture medium at graded concentrations ranging from 2.5 11M to 125 11M, LDH leakage was found to be suppressed. The suppression became more marked as the magnesium lithospermate B concentration increased, with leakage in the presence of 125 11M magnesium lithospermate B being comparable to that in the absence of cisplatin. This suppressive effect of magnesium lithospermate B on LDH leakage was also noted in culture medium devoid of cisplatin, suggesting that magnesium lithospermate B protects cells against oxidative stress when cultured in an atmosphere of 95 % air and 5 % CO 2 •
'
The MDA released from LLC-PK, cells also showed behavior similar to that observed with the LDH activity. On the other hand, SUGIHARA et al. (1987) and HANNEMANN and BAUMANN (1988) studied the mechanisms of renal injury induced by cisplatin using rat renal cortical sections, and reported that cisplatin induced an increase in the production of lipid peroxides and disturbance of renal cell function. McGUINESS et al. (1978) suggested that free radicals were involved in the development of cisplatin-induced renal injury, since the injury was ameliorated by superoxide dismutase (SOD). GEMBA et al. (1991) also arrived at a same conclusion from the finding that the hydroxyl radical (·OH) scavenger N,N'-dimethyl thiourea ameliorated cisplatin-induced renal injury. In a previous study using nephrectomized rats, we found that SOD and catalase activities were increased significantly after administration of magnesium lithospermate B, whereas they remained low in rats given no magnesium lithospermate B; electron spin resonance spectroscopy combined with spin-trapping using 5,5-dimethyl-l-pyrroline-N-oxide (DMPO) also showed that magnesium lithospermate B eliminated radicals belonging to the DMPO adduct ·OH (DMPO-OH) (YOKOZAwA et al. 1997). These findings suggest that radicals are involved in the suppressive effect of magnesium lithospermate B on cisplatin cytotoxicity.
References BLACHLEY JD, HILL JB : Renal and electrolyte disturbance associated with cisplatin. Ann Intern Med 1981; 95: 628-632. GASTRAUNTHALER GJA: Epithelial cells in tissue culture. Renal Physiol Biochem 1988; 11: 1-42. GEMBA M: Cisplatin-induced acute renal failure. Kidney and Dialysis 1991; 31 (special vol): 421-425. Exp Toxic Pathol 49 (1997) 5
345
GEMBA M, FUKUISHI N: Amelioration by ascorbic acid of cisplatin-induced injury in cultured renal epithelial cells. In KOIDE H, ENDOU H, KUROKAWA K (eds.): Cellular and Molecular Biology of the Kidney. Contributions to Nephrology. S. Karger, Basel 1991, pp. 138-142. GEMBA M, MATSUSHITA T, FUJISAWA C et a1.: Enhancement by glutathione depletion of cisplatin-induced nephrotoxicity in rats: Effect of antioxidant pretreatment. In BACH PH, GREGG NJ, WILKS MF et a1. (eds.): Nephrotoxicity. Marcel Dekker, New York 1991, pp. 315-320. GOLDSTEIN RS, MAYOR GH: The nephrotoxicity of cisplatin. Life Sci 1983; 32: 685-690. HANNEMANN J, BAUMANN K: Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: Different effects of antioxidants and radical scavengers. Toxicology 1988; 51: 119-132. LITTERST CL: Cisplatinum: A review, with special reference to cellular and molecular interactions. Agents and Actions 1984; 15: 520-524. MCGUINESS JE, PROCTOR PH, DEMOPOULOS HB et a1.: Amelioration of cis-platinum nephrotoxicity by Orgotein (superoxide dismutase). Physiol Chern Phys 1978; 10: 267-277. SUGIHARA K, NAKANO S, GEMBA M: Effect of cisplatin on in vitro production of lipid peroxides in rat kidney cortex. Jpn J Pharmacol1987; 44: 71-76. TANAKA T, MORIMOTO S, NONAKA G et a1.: Magnesium and ammonium-potassium lithospermates B, the active principles having a uremia-preventive effect from Salvia miltiorrhiza. Chern Pharm Bull 1989; 37: 340-344.
Exp Toxic Pathol 1997; 49: 346 Gustav Fischer Verlag
WEINER MW, JACOBS C: Mechanism of cisplatin nephrotoxicity. Federation Proc 1983; 42: 2974--2978. YAGI K: A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 1976; 15: 212-216. YOKOZAWA T, OURA H, LEE TW et a1.: Augmentation of renal response by magnesium lithospermate B. Nephron 1991a; 57: 78-83. YOKOZAWA T, CHUNG HY, LEE TW et a1.: Potentiating effect of converting enzyme inhibitor captopril to the renal responses of magnesium lithospermate B in rats with adenine-induced renal failure. Chern Pharm Bull 1991 b; 39: 732-736. YOKOZA wAT, LEE TW, OURA H et a1.: Effect of magnesium lithospermate B in rats with sodium-induced hypertension and renal failure. Nephron 1992a; 60: 460-465. YOKOZAWA T, LEE TW, OURA H et a1.: Haemodynamic effects of magnesium lithospermate B in rats with renal failure. PhytotherRes 1992b; 6: 194-199. YOKOZAWA T, LEE Tw, OURA H et a1.: Renal responses to magnesium lithospermate B in rats with adenine-induced renal failure. Phytother Res 1993a; 7: 235-239. YOKOZAwAT, LEE TW, OURA H et a1.: Effect of magnesium lithospermate B on the renal and urinary kallikrein activities in rats with adenine-induced renal failure. Jpn J Nephrol 1993b;35: 337-342. YOKOZAWA T, DONG E, OURA H et a1.: Magnesium lithospermate B suppresses the increase of active oxygen in rats after subtotal nephrectomy. Nephron 1997; 75: 88-93.
Book review
Verhandlungen der Deutschen Gesellschaft fiir Pathologie 80. Tagung in Dresden
Edited by G. KLOPPEL 768 pages with 121 figures and 62 tables. Gustav Fischer Verlag Jena - Stuttgart - Lubeck - Ulm 1996. Price: DM 390.-; oS 2847.-; sFr 374.50. ISBN 3-437-21148-X. ISSN 0070-4113
The 80th meeting of the German Society of Pathology was held from May, 27th-June 1st 1996 in Dresden. It took place for second time in that town and it was the first session in one of the "new" German countries. Autoimmune disease were the main subject of this session and this theme is reflected in 73 papers. A large number of them are devoted to autoimmune mechanisms in diseases of the gastrointestinal tract and diseases of the skin. So they are helpful for the daily diagnostic problems in these fields. Additionally a large number of reports deal with new aspects in Uropathology, Gynecopathology, Endocrine Patho346
Exp Toxic Pathol49 (1997) 5
logy, Pedopathology, Dermatopathology, Neuropathology and tumours of the soft tissues and other neoplasms. The working group Experimental Pathology reports in 43 lectures about new methods and insights, the working group Cytopathology presents 46 lectures. The 27. Herbsttagung in Mainz is reflected in 641essions with different themes about new development in Pathology. Beside these scientific papers one should regard the ideas about general trends in Pathology ofK. H. Miiller-Hermelink in his opening address. In summary, these "Proceedings" give an actual and useful overview about the selected topics and are recommended. E. SCHULZE, Jena
'Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan 2Faculty of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan
Magnesium lithospermate B ameliorates cisplatin-induced injury in cultured renal epithelial cells TAKAKO YOKOZAWA', ERBO DONG', HIKOKICHI OURA', GEN-ICHIRO NONAKA 2 , and ITSUO NISHIOKA 2 With 3 figures Received: March 30, 1996; Revised: June 26, 1996; Accepted: July 11, 1996 Address for correspondence: Dr. TAKAKO YOKOZAWA, Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0 I , Japan. Key words: Magnesium lithospermate B; Cisplatin; Renal injury; Malondialdehyde; Lactate dehydrogenase; LLC-PK,.
Summary A study was conducted to clarify whether magnesium Iithospermate B ameliorates cisplatin-induced renal injury in terms of lactate dehydrogenase and malondialdehyde leakage from LLC-PK, cells in culture. Magnesium lithospermate B was shown to suppress the cytotoxicity of cisplatin, the suppressive effect increasing with the dose of magnesium lithospermate B.
In the present study using cultured cells, we investigated whether or not magnesium lithospermate B, which is known to ameliorate through the reduction of uremic toxins such as urea nitrogen, creatinine, methyl guanidine and guanidinosuccinic acid in adenine-induced renal failure rats, an animal model of renal tubular impairment (YOKOZA w A et al. 1991 a, 1991 b, I 992a, 1992b, 1993a, 1993b), is also effective against cisplatin-induced renal injury.
Introduction Material and methods cis-Diamminedichloroplatinum (cisplatin) is a platinum chelate having high antitumor activity against carcinomas of the testis, ovary, urinary bladder, prostate, head and neck. However, it has adverse side effects on the kidney, bone marrow and digestive organs. In particular, the risk of renal injury limits the use of this drug in a clinical setting (BLACHLEY and HILL 1981; GOLDSTEIN and MAYOR 1983; WEINER and JACOBS 1983; LITTERST 1984). To enhance the therapeutic antitumor effect of cisplatin while suppressing its injurious effect on the kidney , its combined use with other drugs such as diuretics and the development of harmless cisplatin derivatives have been attempted by many researchers (GEMBA 1991). On the other hand, in various fields including nephrology efforts have been made to establish in vitro experimental systems which do not require complete in vivo animal models. GEMBA and FUKUISHI (1991), using cultured renal tubular cells, have demonstrated that lactate dehydrogenase (LDH) leaks into the culture medium in the presence of cisplatin, and that the cells are damaged at concentrations of cisplatin close to its therapeutic level in blood.
Medium and reagents: Dulbecco's modified Eagle medium/nutrient mixture F-12 (D-MEM/F-12) and fetal calf serum (FCS) were purchased from Life Technologies, Inc. (Grand Island, NY, USA) and Cell Culture Laboratories (Cleveland, OH, USA), respectively. Cisplatin was obtained from Sigma Chemical Co. (St. Louis, MO, USA). LDH and malondialdehyde (MDA) leakage assay: LLCPK, cells were maintained at 37 °C in a humidified atmosphere of 5 % CO 2 in air in 96-well culture plates (Corning Glass Works, Corning, NY) with 5 % FCS-supplemented D-MEMIF-12 medium. After confluence had been reached, the cells were seeded in culture plates at 104 per well. Cisplatin and/or magnesium lithospermate B were added to the culture 2 h later, and the plates were incubated for 48 h. Leakage ofLDH into the culture medium was assayed as an index of cytotoxicity using a commercial kit from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). The extent of lipid peroxidation was estimated by measuring the concentration of MDA as described by YAGI (1976). Purification of magnesium lithospermate B from Salviae Miltiorrhizae Radix: As reported previously (TANAKA et al. 1989), commercially available Salviae Miltiorrhizae Exp Toxic Pathol49 (1997) 5
343
Radix (Salvia Miltiorrhiza BUNGE) (1.0 kg) produced in China was extracted twice with water (1.5 liters) at 80°C. After removal of insoluble matter by filtration, the filtrate was concentrated under reduced pressure (40°C) and subjected to MCI-gel CHP-20P (7.5 cm i.d. x 35 cm) column chromatography. After washing the column with water, elution with 50 % aqueous methanol yielded polyphenols (62 g), which were chromatographed using a Sephadex LH-20 column (5.0 cm i. d. x 42 cm) with water containing increasing amounts of ethanol to afford three fractions: I (4.8 g), II (0.35 g) and III (5.9 g), and compound 1 (7.56 g). Fractions I and III were rechromatographed separately on a Sephadex LH-20 column using water as an eluent to yield compound 2 (1.98 g) and a further fraction of compound 1 (4.3 g). Compound 1 was identified as magnesium lithospermate B on the basis of its \3C nuclear magnetic resonance spectrum, infrared spectrum, negative fast-atom bombardment mass spectrum, proton nuclear magnetic resonance spectrum, energy-dispersive X-ray analysis and other data. Its chemical structure is shown in fig. 1. Statistics: Results are presented as mean ± S. E. of 5 determinations. The data were analyzed for statistical signifi-
OH
cance using DUNNETI'S method. Differences at p < 0.05 were considered statistically significant.
Results As shown in fig. 2, LDH leakage from the cells into the culture medium increased after cisplatin had been added to the medium. Although there was no suppression of the cytotoxic effect of cisplatin in the presence of 2.5 11M magnesium lithospermate B, 12.5 11M suppressed the leakage significantly to 231.5 mID/m!. This suppression became more marked as the concentration of magnesium lithospermate B increased, the LDH activity (128.5 mID/ml) in the presence of 125 11M magnesium litho sperm ate B being comparable to that in the absence of cisplatin (116.6 mID/ml). When the effect of magnesium lithospermate B was examined in the absence of cisplatin, LDH leakage into the culture medium was found to be suppressed in a dose-dependent manner (fig. 2). Similar
OH OH
Fig. 1. Structural formula of magnesium lithospermate B.
300
~ ! .;:
..
250
200
~
t
150
til
==
100
~
50
Q
o Fig.2. Effect of cisplatin and magnesium lithospermate B (MLB) on LDH leakage from LLC-PK 1 cells. Statistical significance: #p < 0.001 vs. valuefor cisplatin only, *p < 0.01, **p < 0.001 vs. value for non-treatment. 344
Exp Toxic Pathol 49 (1997) 5
Fig. 3. Effect of cisplatin and magnesium lithospermate B (MLB) on MDA released from LLC-PK 1 cells. Statistical significance: #p < 0.001 vs. value for cisplatin only, *p < 0.05, **p < 0.01, ***p < 0.001 vs. value for non-treatment.
changes produced by magnesium lithospermate B were observed in the MDA values (fig. 3).
Discussion There is an urgent need to establish in vitro experimental systems which can replace in vivo animal models for analysis of drug actions and toxicity studies. Efforts in this direction have also been made in the field of nephrology. Among various established renal epithelial cell lines, hog-derived LLC-PK 1 cells are considered to be similar in character to the proximal uriniferous tubule, and MDCK cells to the distal uriniferous tubule and collecting tubule in the renal cortex (GASTRAUNTHALER 1988). Since it is known that cisplatin acts mainly on the straight part of the proximal uriniferous tubule, we used LLC-PK cells to . mvestigate the effect of magnesium lithospermate B on cisplatin-induced renal injury. The effect was determined in terms of the leakage of the lysosomal enzyme LDH from these cells into the culture medium through their damaged plasma membranes. It was found that the amount of LDH leakage from LLC-PK 1 cells was about 2A-fold greater in the presence of 0.25 11M cisplatin than in the absence of cisplatin, demonstrating the cytotoxicity of this drug. When magnesium lithospermate B was also present in the culture medium at graded concentrations ranging from 2.5 11M to 125 11M, LDH leakage was found to be suppressed. The suppression became more marked as the magnesium lithospermate B concentration increased, with leakage in the presence of 125 11M magnesium lithospermate B being comparable to that in the absence of cisplatin. This suppressive effect of magnesium lithospermate B on LDH leakage was also noted in culture medium devoid of cisplatin, suggesting that magnesium lithospermate B protects cells against oxidative stress when cultured in an atmosphere of 95 % air and 5 % CO 2 •
'
The MDA released from LLC-PK, cells also showed behavior similar to that observed with the LDH activity. On the other hand, SUGIHARA et al. (1987) and HANNEMANN and BAUMANN (1988) studied the mechanisms of renal injury induced by cisplatin using rat renal cortical sections, and reported that cisplatin induced an increase in the production of lipid peroxides and disturbance of renal cell function. McGUINESS et al. (1978) suggested that free radicals were involved in the development of cisplatin-induced renal injury, since the injury was ameliorated by superoxide dismutase (SOD). GEMBA et al. (1991) also arrived at a same conclusion from the finding that the hydroxyl radical (·OH) scavenger N,N'-dimethyl thiourea ameliorated cisplatin-induced renal injury. In a previous study using nephrectomized rats, we found that SOD and catalase activities were increased significantly after administration of magnesium lithospermate B, whereas they remained low in rats given no magnesium lithospermate B; electron spin resonance spectroscopy combined with spin-trapping using 5,5-dimethyl-l-pyrroline-N-oxide (DMPO) also showed that magnesium lithospermate B eliminated radicals belonging to the DMPO adduct ·OH (DMPO-OH) (YOKOZAwA et al. 1997). These findings suggest that radicals are involved in the suppressive effect of magnesium lithospermate B on cisplatin cytotoxicity.
References BLACHLEY JD, HILL JB : Renal and electrolyte disturbance associated with cisplatin. Ann Intern Med 1981; 95: 628-632. GASTRAUNTHALER GJA: Epithelial cells in tissue culture. Renal Physiol Biochem 1988; 11: 1-42. GEMBA M: Cisplatin-induced acute renal failure. Kidney and Dialysis 1991; 31 (special vol): 421-425. Exp Toxic Pathol 49 (1997) 5
345
GEMBA M, FUKUISHI N: Amelioration by ascorbic acid of cisplatin-induced injury in cultured renal epithelial cells. In KOIDE H, ENDOU H, KUROKAWA K (eds.): Cellular and Molecular Biology of the Kidney. Contributions to Nephrology. S. Karger, Basel 1991, pp. 138-142. GEMBA M, MATSUSHITA T, FUJISAWA C et a1.: Enhancement by glutathione depletion of cisplatin-induced nephrotoxicity in rats: Effect of antioxidant pretreatment. In BACH PH, GREGG NJ, WILKS MF et a1. (eds.): Nephrotoxicity. Marcel Dekker, New York 1991, pp. 315-320. GOLDSTEIN RS, MAYOR GH: The nephrotoxicity of cisplatin. Life Sci 1983; 32: 685-690. HANNEMANN J, BAUMANN K: Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: Different effects of antioxidants and radical scavengers. Toxicology 1988; 51: 119-132. LITTERST CL: Cisplatinum: A review, with special reference to cellular and molecular interactions. Agents and Actions 1984; 15: 520-524. MCGUINESS JE, PROCTOR PH, DEMOPOULOS HB et a1.: Amelioration of cis-platinum nephrotoxicity by Orgotein (superoxide dismutase). Physiol Chern Phys 1978; 10: 267-277. SUGIHARA K, NAKANO S, GEMBA M: Effect of cisplatin on in vitro production of lipid peroxides in rat kidney cortex. Jpn J Pharmacol1987; 44: 71-76. TANAKA T, MORIMOTO S, NONAKA G et a1.: Magnesium and ammonium-potassium lithospermates B, the active principles having a uremia-preventive effect from Salvia miltiorrhiza. Chern Pharm Bull 1989; 37: 340-344.
Exp Toxic Pathol 1997; 49: 346 Gustav Fischer Verlag
WEINER MW, JACOBS C: Mechanism of cisplatin nephrotoxicity. Federation Proc 1983; 42: 2974--2978. YAGI K: A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 1976; 15: 212-216. YOKOZAWA T, OURA H, LEE TW et a1.: Augmentation of renal response by magnesium lithospermate B. Nephron 1991a; 57: 78-83. YOKOZAWA T, CHUNG HY, LEE TW et a1.: Potentiating effect of converting enzyme inhibitor captopril to the renal responses of magnesium lithospermate B in rats with adenine-induced renal failure. Chern Pharm Bull 1991 b; 39: 732-736. YOKOZA wAT, LEE TW, OURA H et a1.: Effect of magnesium lithospermate B in rats with sodium-induced hypertension and renal failure. Nephron 1992a; 60: 460-465. YOKOZAWA T, LEE TW, OURA H et a1.: Haemodynamic effects of magnesium lithospermate B in rats with renal failure. PhytotherRes 1992b; 6: 194-199. YOKOZAWA T, LEE Tw, OURA H et a1.: Renal responses to magnesium lithospermate B in rats with adenine-induced renal failure. Phytother Res 1993a; 7: 235-239. YOKOZAwAT, LEE TW, OURA H et a1.: Effect of magnesium lithospermate B on the renal and urinary kallikrein activities in rats with adenine-induced renal failure. Jpn J Nephrol 1993b;35: 337-342. YOKOZAWA T, DONG E, OURA H et a1.: Magnesium lithospermate B suppresses the increase of active oxygen in rats after subtotal nephrectomy. Nephron 1997; 75: 88-93.
Book review
Verhandlungen der Deutschen Gesellschaft fiir Pathologie 80. Tagung in Dresden
Edited by G. KLOPPEL 768 pages with 121 figures and 62 tables. Gustav Fischer Verlag Jena - Stuttgart - Lubeck - Ulm 1996. Price: DM 390.-; oS 2847.-; sFr 374.50. ISBN 3-437-21148-X. ISSN 0070-4113
The 80th meeting of the German Society of Pathology was held from May, 27th-June 1st 1996 in Dresden. It took place for second time in that town and it was the first session in one of the "new" German countries. Autoimmune disease were the main subject of this session and this theme is reflected in 73 papers. A large number of them are devoted to autoimmune mechanisms in diseases of the gastrointestinal tract and diseases of the skin. So they are helpful for the daily diagnostic problems in these fields. Additionally a large number of reports deal with new aspects in Uropathology, Gynecopathology, Endocrine Patho346
Exp Toxic Pathol49 (1997) 5
logy, Pedopathology, Dermatopathology, Neuropathology and tumours of the soft tissues and other neoplasms. The working group Experimental Pathology reports in 43 lectures about new methods and insights, the working group Cytopathology presents 46 lectures. The 27. Herbsttagung in Mainz is reflected in 641essions with different themes about new development in Pathology. Beside these scientific papers one should regard the ideas about general trends in Pathology ofK. H. Miiller-Hermelink in his opening address. In summary, these "Proceedings" give an actual and useful overview about the selected topics and are recommended. E. SCHULZE, Jena