Abstract:
:Rabbit bone marrow mitochondria, stripped of their outer membrane (mitoplasts), have been shown to carry out the NADPH-dependent bioactivation of radiolabelled benzene in vitro to metabolites capable of covalently binding to mtDNA, thereby inhibiting transcription. The metabolites of benzene produced in bone marrow cells by the microsomal cytochrome P-450 are thought to be phenol, catechol, hydroquinone and p-benzoquinone (Andrews et al., Life Sci., 25 (1979) 567; Irons et al., Chem.-Biol. Interact., 30 (1980) 241). Incubation of mitoplasts from rabbit bone marrow cells in vitro with varying concentrations of the putative microsomal metabolites showed a concentration-dependent inhibition of RNA synthesis. The 50% inhibitory molar concentration (IC50) for each metabolite was determined to be: 1,2,4- benzenetriol , 6.3 X 10(-7); p-benzo-quinone, 2 X 10(-6); phenol, 2.5 X 10(-5); hydroquinone, 5 X 10(-5); catechol, 2 X 10(-3); benzene, 1.6 X 10(-2). DNA, isolated from rabbit bone marrow cell or rat liver mitoplasts prelabelled in DNA with [3H]dGTP and exposed to [14C]benzene in vitro, was enzymatically hydrolyzed to nucleosides which were chromatographed on a Sephadex LH-20 column to separate free nucleosides from nucleoside-adducts. The elution profiles indicated that rat liver mtDNA contained six guanine nucleoside-adducts and rabbit bone marrow cell mtDNA contained seven guanine nucleoside-adducts. Incubation of bone marrow mitoplasts in vitro in the presence of benzene and the hydroxyl radical scavenger, mannitol, resulted in the inhibition of formation of four of the guanosine-adducts. When [3H]dATP was substituted as the prelabelled precursor nucleotide, the LH-20 column profile indicated that two adenine nucleoside-adducts were also formed from benzene in vitro. Furthermore, a comparison of the Sephadex LH-20 column profiles of purine adducts derived from [14C]benzene- and [3H]dGMP-labelled mtDNA with profiles generated by individually incubating each of the putative unlabelled metabolites with bone marrow mitoplasts in vitro has indicated that p-benzoquinone, phenol, hydroquinone and 1,2,4- benzenetriol form adducts with guanine. One of the two adenosine-adducts may arise from hydroquinone; the compound forming the other adduct is unknown at the present time. Exposure of mitoplasts to catechol in vitro resulted in the formation of a guanine nucleoside-adduct that was present in rat liver mtDNA but absent from the DNA isolated from rabbit bone marrow cell mitoplasts exposed to [14C]benzene in vitro. This suggests that catechol is probably not a major metabolite of benzene formed in bone marrow cell mitochondria.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Rushmore T,Snyder R,Kalf Gdoi
10.1016/0009-2797(84)90057-7subject
Has Abstractpub_date
1984-04-01 00:00:00pages
133-54issue
1-2eissn
0009-2797issn
1872-7786pii
0009-2797(84)90057-7journal_volume
49pub_type
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
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更新日期:2013-01-25 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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更新日期:1993-09-01 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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更新日期:1979-08-01 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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更新日期:2002-05-20 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2004.09.014
更新日期:2004-12-07 00:00:00
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journal_title:Chemico-biological interactions
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更新日期:2019-04-25 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(88)90008-7
更新日期:1988-01-01 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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更新日期:1983-11-01 00:00:00
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journal_title:Chemico-biological interactions
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更新日期:2003-02-01 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(88)90070-1
更新日期:1988-01-01 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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更新日期:2000-03-01 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(75)90100-3
更新日期:1975-09-01 00:00:00
abstract::We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet co...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2005.10.104
更新日期:2006-01-05 00:00:00