PubMed · 6828113
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F A LaVecchio, H M Pashayan, W Singer. 1983-03-24. Agent Orange and birth defects.. https://doi.org/10.1056/nejm198303243081211
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Peroxisome proliferators are known to modulate the activity of xenobiotic-metabolising enzymes, including glutathione S-transferase (GST) and cytochrome P-450 (CYP). In this study the effect of peroxisome proliferators silvex and di(2-ethylhexyl)phthalate (DEHP) on the formation of (+)-anti-benzo(a)pyrene -7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts from a proximate mutagen and carcinogen (-)-transbenzo(a)pyrene-7,8-dihydrodiol (BPDD) has been investigated. Rat CYP1A1 metabolises BPDD to mutagenic BPDE, which may form DNA adducts or, alternatively, be detoxified by hydrolysis or glutathione conjugation. In this experiment the formation of BPDE-DNA adducts was significantly increased in hepatocytes isolated from all silvex treated rats and two out of four DEHP treated rats (14 day treatment). The activity of CYP1A1 was increased whereas GST was reduced by the peroxisome proliferator silvex. These changes were more significant than those induced by DEHP. We have hypothesised that the formation of BPDE-DNA adducts was primarily due to the increased BPDD activation to BPDE versus reduced detoxication of BPDE. Other hepatic changes induced by the peroxisome proliferators, e.g. peroxisome proliferation per se and increased mitotic activity of the liver could have an effect on the outcome of BPDD exposure.
Hydroxyquinol 1,2-dioxygenase, an intradiol dioxygenase, which catalyzes the cleaving of the aromatic ring of hydroxyquinol, a key intermediate of 2,4-D and 2,4,5-T degradation, was purified from Nocardioides simplex 3E cells grown on 2,4-D as the sole carbon source. This enzyme exhibits a highly restricted substrate specificity and is able to cleave hydroxyquinol (K(m) for hydroxyquinol as a substrate was 1.2 microM, V(max) 55 U/mg, K(cat) 57 s-1 and K(cat)/K(m) 47.5 microM s-1), 6-chloro- and 5-chlorohydroxyquinol. Different substituted catechols and hydroquinones are not substrates for this enzyme. This enzyme appears to be a dimer with two identical 37-kDa subunits. Protein and iron analyses indicate an iron stoichiometry of 1 iron/65 kDa homodimer, alpha2 Fe. Both the electronic absorption spectrum which shows a broad absorption band with a maximum at 450 nm and the electron paramagnetic resonance spectra are consistent with a high-spin iron(III) ion in a rhombic environment typical of the active site of intradiol cleaving enzymes.
BACKGROUND: In mice, fibrates induce mdr2 gene expression, and its encoded P-glycoprotein in the canalicular domain of hepatocytes, as well as increasing biliary phospholipid output. It is not known whether this effect is restricted to fibrates or is a common property of peroxisome proliferators. AIMS: To test the effect of structurally unrelated peroxisome proliferators on mdr2 gene expression and biliary phospholipid output, and to explore the molecular mechanism(s) of mdr2 gene induction. METHODS: Male CFI mice were fed on a diet supplemented with several peroxisome proliferators: phenoxyacetic acid herbicides, plasticizers, acetylsalicylic acid and partially hydrogenated fish oil. RESULTS: Increased levels of mdr2 mRNAs, assessed by Northern blot analysis, were observed in the liver of mice treated with phenoxyacetic acid herbicides: 2,4,5-trichlorophenoxyacetic acid 570+/-133%, 2,4-dichlorophenoxyacetic acid 233+/-54% (p<0.005); plasticizers: di-(2-ethylhexyl)phthalate 282+/-78%, di-(isoheptyl)phthalate 163+/-40%, phthalic acid dinonyl ester 225+/-48% (p<0.01); and partially hydrogenated fish oil 372+/-138% (p<0.005). P-glycoprotein traffic ATPase content increased in the canalicular domain of hepatocyte of mice treated with the herbicide 2,4,5-trichlorophenoxyacetic acid and with partially hydrogenated fish oil (108% and 87%, respectively, p<0.05) as well as biliary phospholipid output (106% and 74%, respectively, p<0.05). In 2,4,5-trichlorophenoxyacetic acid-fed mice we found five-fold increase on mdr2 transcription rate, assessed by nuclear run-off assay. CONCLUSIONS: Peroxisome proliferators induce mdr2 gene, its encoded P-gp in the canalicular domain of hepatocytes and increase biliary phospholipid output. The modulation of mdr2 gene might be part of the pleiotrophic response of peroxisome proliferation in mice liver and seems to be regulated mainly at a transcriptional level.