Monoclonal antibody-directed characterization of cytochrome P450 isozymes responsible for toluene metabolism in rat liver

Nakajima, Tamie; Wang, Rui-Sheng; Elovaara, Eivor; Park, Sang S.; Gelboin, Harry V.; Hietanen, Eino; Vainio, Harri

doi:10.1016/0006-2952(91)90536-e

Cited by 67 publications

(27 citation statements)

References 18 publications

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“…The effects of chemicals known to serve as substrates for different cytochrome oxidases, upon NADPH-stimulated ROS, were tested. These Bl' 43,1.f included phenobarbital (100 mM), ethanol (100 mM), and toluene (22 mM) [13][14][15][16]. While ethanol quenched basal microsomal ROS generation at the concentration used, the other substrates did not alter this function significantly.…”

Section: Resultsmentioning

confidence: 99%

Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species

Bondy

Naderi

1994

Biochemical Pharmacology

220

112

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Section: Resultsmentioning

confidence: 99%

Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species

Bondy

Naderi

1994

Biochemical Pharmacology

220

112

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“…It has not been shown what isozyme is responsible for the initial oxidation of the TMBs. The corresponding biotransformation of toluene and m-xylene, however is catalysed by the CYP2E1 isozyme (59,67).…”

Section: Toxicokineticsmentioning

confidence: 99%

“…It is not known which isoform of the P-450 system is involved in the oxidation of TMBs. However, the ethanol-inducible CYP2E1 has been found to oxidise many relatively small molecules like organic solvents, among them toluene and xylene (59,67).…”

Section: Eliminationmentioning

confidence: 99%

Toxicokinetics of Inhaled Trimethylbenzenes in Man

Järnberg

Johanson

Löf

1996

Toxicology and Applied Pharmacology

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“…(1991) showed that isolated cytochrome P·450 fractions (not identified) were able to mctabolizeOTA. Hietanen et al (1991) showed that a cytochrome P-450 isozyme similar to that induced by 3MC is responsible for OTA metabolism. None of the above studies were of sufficient det.nilto examine under the same experimental conditions the effect of several major cytochrome P-450 inducers on OTA metabolism.…”

Section: Daymentioning

confidence: 99%

Effect of cytochrome P450 induction on the metabolism and toxicity of ochratoxin A

Omar

Gelboin

Rahimtula

1996

Biochemical Pharmacology

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The role of cytochrome P-450 in me stimulation of lipid peroxidation induccd by thc mycotoxin ochratoxin A (OTA) has been investigated. Purified cytochrome P-450 (liB I) could effectively replace EDTA in stimulating lipid pefOxidation in a reconstituted system l'Onsisling of phospholipid vesicles, NADPH-cYlochrome P-450rcduc!ase, FeJ+, EDTA and NADPll, suggesting that it could mediate the transfer of electrons from NADPH to foc3,. Microsomcs isolated from liven of cobalt protoporphyrin IX-treated rllts (in which cytochrome P-450 Wll" depletedj underwent OTA-dependent lipid peroxidation much more slowly tlmn control microsomes.The role of cytochrome P-450 in OTA met.1bolism was also investigated. To dClermine which cytochrome P·450 isoforms are involved in the metabolism ofOTA, we used different cytochrome P-450 inducers to induce the major isofonns of cytochrome 1'-450 in lhe rm liver.Microsomes from these livers were used to investigate their effect on OTA metabolism.Pretreatment ofmts with pregnenolone -16c(·carbonitrile (peN), phenobarbit.ll (PB), 3-ll1cthyl cholanthrene (3MC), and isosafrole (ISF) greatly induced 4(R)-4-0H-OTA fonmllion; 4(5)-4-011-OTA fonnation was also induced after pretreatment with PB, PCN, 3MC and ISr:. INII pretreaunem primarily induced me 4(5) isomer formation, The fonnation of the 4(R) .md 4 (5) isomeri showed significant differences with respect to pH optima, effect of antioKidants ami iron chelators, The 4(R) isomer fonnation showed a pH optimum of 6.0 using microsornes from rJIs treated with 3MC and ISF, and 6.5 using mierosomes from rats treated with PI] :tnd peN and Wi!S not inhibited by antioxidants or iron chelators. In contmst, both the 4(5) isomer fonmllion and lipid pcroxidation showed a pH optimum of 7.0 -7,5 and both activities were highly sensitive to inhibition by antioxidants and iron ehelators. Lipid peroxides were no: involved in the 4(5) isomer fonnation since addition of linoleic acid hydroperoxidc to microsomcs did not give rise 10 the 4(5) isomer, Cytochrome P-450 appeared to be essenlial since other hemoprolcins such as horseradish peroxidase and hemoglobin were ineffective in metabolizing OTA. Microsomes from rats pretreated with Co-protoporphyrin IX resulted in no metabolil,rn of ochratoxin A. 7-Ethoxy-and 7-pentoxyresorufin assays showed specificity towards cytochromes P-450 induced by 3MC (fA I/lA2) and PB (IIBI) respectively. Also, metyrapone (inhibitor of cytochrome P·450 IIBt) preferentially inhibited OTA mel1bolism by microsomes from rats treated with PB, and I(-naphthoflavone (inhibitor of cytochrome P-450 IAI/lA2) preferentially inhibited OTA metabolism by microwmes from 3MC and ISF treated rats_ Monoclonal antibodies (MAbs) 1-7-1 (against P-450 lA 1/lA2) and 2-66-3 (against P-450 liB I) showed preferential inhibition ofOTA metabolism by microsomes from 3MC and PB treated rats respectively.Excretion of renal enzymes in urine is a sensitive non-invasive index of renal dam:lge.Therefore. we examined the effect of cytochrome P-450 induction on the...

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Monoclonal antibody-directed characterization of cytochrome P450 isozymes responsible for toluene metabolism in rat liver

Cited by 67 publications

References 18 publications

Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species

Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species

Toxicokinetics of Inhaled Trimethylbenzenes in Man

Effect of cytochrome P450 induction on the metabolism and toxicity of ochratoxin A

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