Comparison of oxidant-generation and BP-diol activation by bone marrow cells from   and   mice: Implications for risk of bone marrow toxicity induced by polycyclic hydrocarbons

Twerdok, Lorraine E.; Mosebrook, D.Randolph; Trush, Michael A.

doi:10.1016/0041-008x(92)90196-y

Cited by 18 publications

(5 citation statements)

References 21 publications

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“…These reactive products of neutrophils produce DNA strand breaks and sister chromatid exchange in neighboring cells (23)(24)(25). Additionally, neutrophils also enhance oxidation of carcinogens to highly reactive metabolic intermediates (34,35). Consequently, blocking formation of LTB 4 or enhancing its catabolism may afford protection from tumorigenesis.…”

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confidence: 99%

Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention

Primiano

Kensler

et al. 1998

Carcinogenesis

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Cancer chemoprevention is inhibition of neoplastic disease by naturally occurring or synthetic chemical agents. Dithiolethiones inhibit production of experimentally produced tumors by elevating the expression of several genes that encode for known cytoprotective enzymes. In an effort to discover additional molecular mechanisms mediating chemoprevention, cDNA clones representing a gene that is transcriptionally activated by dithiolethiones, hence named dithiolethione-inducible gene-1 (DIG-1), were isolated from rat liver via differential hybridization screening. The deduced amino acid sequence of DIG-1 was found to have 80% identity with the human liver enzyme leukotriene B 4 (LTB 4 ) 12-hydroxydehydrogenase. DIG-1, purified >400-fold from the liver of rats dosed with 1,2-dithiole-3-dithiolethione, possessed an NADP ⍣ -dependent activity to convert LTB 4 to 12-oxo-LTB 4 . Kinetic analysis of DIG-1 revealed apparent K m and V max values of 28 mM and 8

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confidence: 99%

Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention

Primiano

Kensler

et al. 1998

Carcinogenesis

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“…The data analyzed in this report, however, are derived from two strains of mice (D2 and BDF1) that, beside the Ah locus difference, differ in numerous other aspects; therefore, there might be other factors that potentially may influence the hematopoietic changes. Twerdok et al (1992) recently suggested that the difference in bone marrow toxicity between DBA/2 and C57BI/6 mice may be related to their ability to bioactivate xenobiotics through oxidant dependent mechanisms. They reported a two-fold enhancement of oxidant-dependent chemiluminescence produced by BaP-diol in stimulated neutrophilic cells from DBA/2 mice as compared to cells from C57BI/6 mice.…”

Section: Model Resultsmentioning

confidence: 99%

A mathematical approach to benzo[a]pyrene-induced hematotoxicity

et al. 1992

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Benzo[a]pyrene (BaP) has been reported to exert a differential effect on murine hematopoiesis that is mouse strain specific. Interpretation of these results based solely on experimental data is restricted and leaves important questions unanswered. Therefore, a mathematical model of murine hematopoiesis was applied in order to: (1) identify the targets of BaP, (2) quantify the damage to target cells and (3) based on these results, interpret differences in strain susceptibility. Model analysis of the hematopoietic response of D2 and BDF1 mice to a daily oral administration of 125 mg/kg BaP showed that proliferating hematopoietic cells are the targets of BaP. Within this group it was found that: (a) erythropoietic cells were the most susceptible to BaP, (b) granulopoietic cells showed a susceptibility half that of erythropoietic cells and (c) the susceptibility of stem cells ranged between that of erythropoietic and granulopoietic cells. This damage pattern was the same for both strains, indicating that the difference between the strains was quantitative. As cell destruction rates were about 3-fold higher for D2 than BDF1 mice, it was concluded that D2 mice were about three times as susceptible to BaP as BDF1 mice. The study showed that the mathematical model, in addition to experimental methods, provided an efficient tool for the analysis of BaP hematotoxicity.

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“…Therefore, nestlings could have metabolized more of the parent compound to toxic products than the orally exposed adults. Alternatively, studies of mice by Twerdok et al [36] and Ladics et al [37] have shown that benzo[a]pyrene-diol is converted to the reactive intermediate, 7,8-dihydroxy-9,10epoxy-7,8,9,1O-tetrahydrobenzo[a]pyrene intracellularly by neutrophils and macrophages, respectively. If this is true, then the observed differences in toxic responses between orally dosed juveniles and sc-dosed adults would be related to differing doses at the cellular level rather than enzyme activity differences in the liver.…”

Section: Discussionmentioning

confidence: 99%

EFFECTS OF 7,12-DIMETHYLBENZ[a]ANTHRACENE ON IMMUNE FUNCTION AND MIXED-FUNCTION OXYGENASE ACTIVITY IN THE EUROPEAN STARLING

Trust¹,

Fairbrother²,

Hooper³

1994

Environ Toxicol Chem

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Immune function and hepatic MFO activity were examined in adult and nestling starlings administered a synthetic PAH, 7,12-dimethylbenz[a]anthracene (DMBA). Methods used to examine the starling immune system included immunopathology, macrophage phagocytosis, lymphocyte blastogenesis to concanavalin A, and hemagglutination of sheep erythrocytes (SRBC). Concomitant investigations of MFO activity were conducted in starlings exposed to DMBA. Ethoxyresorufin 0-dealkylase (EROD) and pentoxyresorufin 0-depentylase (PROD) were used as indicators of hepatic MFO activity. Changes in MFO activity were compared to chemically altered immune responses following DMBA exposure. Subcutaneous exposure of adult starlings to 125 mg/kg DMBA resulted in suppression of lymphocyte blastogenesis and antibody production to SRBC. EROD and PROD activity were increased 2.8-and 3.4-fold, respectively. Lymphocyte blastogenesis was impaired in adult starlings orally exposed to 125 mg/kg DMBA. The immune system of nestling starlings exposed orally to 100 mg/kg DMBA was altered, as evidenced by decreased phagocytic ability of macrophages and inhibition of lymphocyte blastogenesis. Oral exposure to DMBA did not induce MFO activity in starlings of either age class. Effects of DMBA on immune function and MFO activity in starlings varied with the age of birds and route and length of chemical exposure.

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Comparison of oxidant-generation and BP-diol activation by bone marrow cells from and mice: Implications for risk of bone marrow toxicity induced by polycyclic hydrocarbons

Cited by 18 publications

References 21 publications

Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention

Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention

A mathematical approach to benzo[a]pyrene-induced hematotoxicity

EFFECTS OF 7,12-DIMETHYLBENZ[a]ANTHRACENE ON IMMUNE FUNCTION AND MIXED-FUNCTION OXYGENASE ACTIVITY IN THE EUROPEAN STARLING

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