Comparative studies on the effects of sodium phenobarbital and two other constitutive androstane receptor (CAR) activators on induction of cytochrome P450 enzymes and replicative DNA synthesis in cultured hepatocytes from wild type and CAR knockout rats

Toxicology ◽  
2020 ◽  
Vol 433-434 ◽  
pp. 152394
Author(s):  
Manuela Goettel ◽  
Ivana Fegert ◽  
Naveed Honarvar ◽  
Audrey Vardy ◽  
Corinne Haines ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Dna Synthesis ◽  
Comparative Studies ◽  
Constitutive Androstane Receptor ◽  
Cultured Hepatocytes ◽  
Wild Type ◽  
Cytochrome P450 Enzymes ◽  
Sodium Phenobarbital

Atropselective Disposition of 2,2',3,4',6-Pentachlorobiphenyl (PCB 91) and Identification of Its Metabolites in Mice with Liver-specific Deletion of Cytochrome P450 Reductase

2019 ◽  
Author(s):  
Xianai Wu ◽  
Guangshu Zhai ◽  
Jerald L. Schnoor ◽  
Hans-Joachim Lehmler
Keyword(s):  
Cytochrome P450 ◽  
Hepatic Metabolism ◽  
Cytochrome P450 Reductase ◽  
Wild Type ◽  
Cytochrome P450 Enzymes ◽  
High Fat ◽  
Hydroxylated Metabolites ◽  
Chiral Polychlorinated Biphenyls ◽  
Specific Deletion

Cytochrome P450 enzymes oxidize chiral polychlorinated biphenyls (PCBs) to hydroxylated metabolites. Here we investigated the role of an impaired hepatic metabolism in the disposition of PCB 91 (CASRN 68194-05-8) in mice with a liver-specific deletion of the cpr gene (KO mice). KO mice and wild type (WT) mice were exposed to racemic PCB 91. Levels and enantiomeric fractions of PCB 91 and its metabolites were determined in tissues 3-days after PCB exposure. PCB 91 were higher in KO compared to WT mice. The liver of KO mice accumulated PCB 91 due to the high fat content in the liver of KO mice. 2,2',3,4',6-Pentachlorobiphenyl-5-ol was the major metabolite detected in all samples. PCB 91 and its metabolites displayed a genotype-dependent atropisomeric enrichment. These differences in atropselective disposition of PCB 91 and its metabolites are consistent with slower metabolism of PCB 91 in KO than WT mice and the accumulation of the parent PCB in the fatty liver of KO mice.<br>

Non-target site mechanism of metribuzin tolerance in induced tolerant mutants of narrow-leafed lupin (Lupinus angustifolius L.)

2012 ◽  
Vol 63 (5) ◽  
pp. 452 ◽  
Author(s):  
Gang Pan ◽  
Ping Si ◽  
Qin Yu ◽  
Jumin Tu ◽  
Stephen Powles
Keyword(s):  
Cytochrome P450 ◽  
Lupinus Angustifolius ◽  
Target Site ◽  
Grain Legume ◽  
Wild Type ◽  
Cytochrome P450 Enzymes ◽  
Tolerance Mechanism ◽  
P450 Monooxygenase ◽  
Gene Target ◽  
Legume Crop

Narrow-leafed lupin (Lupinus angustifolius L.) is an important grain legume crop in Australia. Metribuzin is an important herbicide used to control weeds in lupin crops. This study investigated metribuzin tolerance mechanism in narrow-leafed lupin by comparing two induced mutants (Tanjil-AZ-33 and Tanjil-AZ-55) of higher metribuzin tolerance with the susceptible wild type. Sequencing of the highly conserved region of the chloroplast psbA gene (target site) revealed that the sequences of the wild type and the mutants were identical and therefore metribuzin tolerance is not target site based. Photosynthetic activity was measured and the leaf photosynthesis of the two tolerant mutants was initially inhibited after metribuzin treatment, but recovered within 2.5 days whereas that of the susceptible plants remained inhibited. The photosynthetic measurements confirmed the target site chloroplast was susceptible and the tolerance mechanism is non-target site based. Investigation with known cytochrome P450 monooxygenase inhibitors (omethoate, malathion and phorate) showed that tolerance could be reversed in both mutants, indicating the tolerance mechanism in two tolerant mutants may involve cytochrome P450 enzymes. Interestingly, the inhibitor tridiphane reversed metribuzin tolerance of only one of the two tolerant mutants, indicating diversity in metribuzin tolerance mechanisms in narrow-leafed lupin. These results signify that further investigation of metribuzin metabolism in these plants is warranted. In conclusion, metribuzin tolerance mechanism in lupin mutants is non-target site based, likely involving P450-mediated metribuzin metabolism.

scholarly journals Atropselective Disposition of 2,2',3,4',6-Pentachlorobiphenyl (PCB 91) and Identification of Its Metabolites in Mice with Liver-specific Deletion of Cytochrome P450 Reductase

2019 ◽  
Author(s):  
Xianai Wu ◽  
Guangshu Zhai ◽  
Jerald L. Schnoor ◽  
Hans-Joachim Lehmler
Keyword(s):  
Cytochrome P450 ◽  
Hepatic Metabolism ◽  
Cytochrome P450 Reductase ◽  
Wild Type ◽  
Cytochrome P450 Enzymes ◽  
High Fat ◽  
Hydroxylated Metabolites ◽  
Chiral Polychlorinated Biphenyls ◽  
Specific Deletion

Cytochrome P450 enzymes oxidize chiral polychlorinated biphenyls (PCBs) to hydroxylated metabolites. Here we investigated the role of an impaired hepatic metabolism in the disposition of PCB 91 (CASRN 68194-05-8) in mice with a liver-specific deletion of the cpr gene (KO mice). KO mice and wild type (WT) mice were exposed to racemic PCB 91. Levels and enantiomeric fractions of PCB 91 and its metabolites were determined in tissues 3-days after PCB exposure. PCB 91 were higher in KO compared to WT mice. The liver of KO mice accumulated PCB 91 due to the high fat content in the liver of KO mice. 2,2',3,4',6-Pentachlorobiphenyl-5-ol was the major metabolite detected in all samples. PCB 91 and its metabolites displayed a genotype-dependent atropisomeric enrichment. These differences in atropselective disposition of PCB 91 and its metabolites are consistent with slower metabolism of PCB 91 in KO than WT mice and the accumulation of the parent PCB in the fatty liver of KO mice.<br>

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