Irgasan(R) DP 300 (5-chloro-2-(2,4-dichlorophenoxy)phenol) induces cytochrome P450s and inhibits haem biosynthesis in rat hepatocytes cultured on Matrigel

被引:23
作者
Jinno, H [1 ]
Hanioka, N [1 ]
Onodera, S [1 ]
Nishimura, T [1 ]
Ando, M [1 ]
机构
[1] SCI UNIV TOKYO, FAC PHARMACEUT SCI, SHINJYUKU KU, TOKYO 163, JAPAN
关键词
D O I
10.1080/004982597240271
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. The effect of Irgasan DP 300 (5-chloro-2-(2,4-dichlorophenoxy)phenol) on cytochrome P450 (P450) induction and haem biosynthesis was studied in rat hepatocytes cultured on Matrigel. 2. Irgasan DP 300 significantly induced 7-benzyloxyresorufin O-debenzylase activity, followed by 7-pentoxyresorufin O-depentylase and 7-ethoxyresorufin O-deethylase activities. 4-Nitrophenol hydroxylase, testosterone 6 beta-hydroxylase and methoxyresorufin O-demethylase activities were also slightly increased. The maximum induction of these enzyme activities was obtained at the same concentration of 125 mu M in the culture medium. 3. Immunochemical blots using anti-rat cytochrome P450 antibodies revealed that Irgasan DP 300 preferably induced CYP2B1/2 along with a slight increase in 3A. These results indicate that Irgasan DP 300 is a phenobarbital-type inducer. 4. In the absence of exogenous 5-aminolevulinic acid (ALA), slight increases in protoporphyrin IX (2.6-fold) and coproporphyrin III (1.3-fold) were observed in the Irgasan DP 300-treated cultures. In contrast, when 75 p mu M ALA was present, Irgasan DP 300 (250 mu M) caused an extensive accumulation of uroporphyrin I (13-fold). 5. Irgasan DP 300 inhibited rat hepatic uroporphyrinogen III synthase in vitro. 6. These results indicate that Irgasan DP 300 produced accumulation of hydroxymethylbilane in rat hepatocytes by inhibiting uroporphyrinogen III synthase, and consequently an accumulation of uroporphyrin I.
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页码:681 / 692
页数:12
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共 42 条
[1]  
BATTERSBY AR, 1982, J CHEM SOC PERK T 1, P2427, DOI 10.1039/p19820002427
[2]   HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC SEPARATION AND QUANTITATION OF TETRAPYRROLES FROM BIOLOGICAL-MATERIALS [J].
BONKOVSKY, HL ;
WOOD, SG ;
HOWELL, SK ;
SINCLAIR, PR ;
LINCOLN, B ;
HEALEY, JF ;
SINCLAIR, JF .
ANALYTICAL BIOCHEMISTRY, 1986, 155 (01) :56-64
[3]   INVITRO INHIBITORY EFFECT ON PORPHYRINOGEN CARBOXYLASE OF LIVER EXTRACTS FROM TCDD TREATED MICE [J].
CANTONI, L ;
DALFIUME, D ;
RIZZARDINI, M ;
RUGGIERI, R .
TOXICOLOGY LETTERS, 1984, 20 (02) :211-217
[4]   RAT HEPATIC UROPORPHYRINOGEN-III CO-SYNTHASE - PURIFICATION, PROPERTIES, AND INHIBITION BY METAL-IONS [J].
CLEMENT, RP ;
KOHASHI, M ;
PIPER, WN .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1982, 214 (02) :657-667
[5]   INCREASED OXIDATION OF UROPORPHYRINOGEN BY AN INDUCIBLE LIVER MICROSOMAL SYSTEM - POSSIBLE RELEVANCE TO DRUG-INDUCED UROPORPHYRIA [J].
DEMATTEIS, F ;
HARVEY, C ;
REED, C ;
HEMPENIUS, R .
BIOCHEMICAL JOURNAL, 1988, 250 (01) :161-169
[6]  
DEYBACH JC, 1981, J LAB CLIN MED, V97, P551
[7]   INCREASED OXIDATION OF PARA-NITROPHENOL AND ANILINE BY INTACT HEPATOCYTES ISOLATED FROM PYRAZOLE-TREATED RATS [J].
DICKER, E ;
MCHUGH, T ;
CEDERBAUM, AI .
BIOCHIMICA ET BIOPHYSICA ACTA, 1990, 1035 (03) :249-256
[8]   RELATIVE POTENCIES OF INDUCTION OF HEPATIC DRUG-METABOLIZING ENZYME GENES BY INDIVIDUAL PCB CONGENERS [J].
DRAGNEV, KH ;
NIMS, RW ;
FOX, SD ;
LINDAHL, R ;
LUBET, RA .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1995, 132 (02) :334-342
[9]  
GOLDSTEIN JA, 1984, MOL PHARMACOL, V25, P185
[10]   EXPERIMENTAL HEPATIC PORPHYRIA INDUCED BY POLYCHLORINATED BIPHENYLS [J].
GOLDSTEIN, JA ;
HICKMAN, P ;
JUE, DL .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1974, 27 (02) :437-448