Chlordane and Heptachlor Are Metabolized Enantioselectively by Rat Liver Microsomes

Kania-Korwel, Izabela; Lehmler, Hans‐Joachim

doi:10.1021/es401916a

Cited by 24 publications

(9 citation statements)

References 56 publications

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“…For example, changes in the hepatic P450 enzyme composition have been shown to alter OH-PCB profiles in in vitro metabolism studies 53, 54 and affect chiral signatures of other chiral environmental pollutants, such as chlordanes. 55, 56 Several animal studies have shown that physiological changes during pregnancy alter the enantioselective disposition of chiral bronchodilators 25 or antidepressants. 26 Moreover, PCBs absorbed from the diet may avoid the atropselective hepatic first-pass metabolism due to differences in the lipoprotein transport during pregnancy, 49 which could also contribute to differences in EF values.…”

Section: Discussionmentioning

confidence: 99%

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Kania-Korwel

Barnhart

Lein

et al. 2015

Chem. Res. Toxicol.

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Chiral PCBs, such as PCB 95, are developmental neurotoxicants that undergo atropisomeric enrichment in non-pregnant, adult mice. Because pregnancy is associated with changes in hepatic cytochrome P450 enzyme activity as well as lipid disposition and metabolism, this study investigates the effect of pregnancy on the maternal disposition of chiral PCBs. Female C57Bl/6 mice (8 weeks old) were dosed daily beginning 2 weeks prior to conception and continuing throughout gestation and lactation (56 days total) with racemic PCB 95 (0, 0.1, 1.0 or 6.0 mg/kg body wt/day) in peanut butter. Levels and chiral signatures of PCB 95 and its hydroxylated metabolites (OH-PCBs) were determined in adipose, blood, brain and liver. Tissue levels of PCB 95 increased 4 to 12 fold with increasing dose, with considerable enrichment of the second eluting atropisomer in all tissues (EF range 0.11 to 0.26). OH-PCBs displayed atropisomeric enrichment in blood and liver, but were not detected in adipose and brain. Levels of PCB 95 and its metabolites were 2 to 11 fold lower in pregnant dams relative to those previously reported in non-pregnant age-matched female mice; however, PCB 95 and OH-PCB profiles and chiral signatures were similar between both studies. In contrast, human brain samples contained racemic PCB 95 residues (EF=0.50). These results demonstrate that changes in cytochrome P450 enzyme activity and lipid disposition during pregnancy reduce the PCB body burden in dams, but do not affect metabolite profiles or chiral signatures. The differences in chiral signatures between mice and humans suggest species-specific differences in atropisomeric disposition, the toxicological significance of which remain to be determined.

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Section: Discussionmentioning

confidence: 99%

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Kania-Korwel

Barnhart

Lein

et al. 2015

Chem. Res. Toxicol.

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“…The less effective enantiomer may cause a burden for the environment and nontarget organisms. Environmental behaviors, such as degradation and accumulation, and metabolism in animals of the pair of enantiomers could be significantly different, resulting in different half‐lives, degradation profiles, and residues 4–6 …”

Section: Introductionmentioning

confidence: 99%

The enantioselective enrichment, metabolism, and toxicity of fenoxaprop‐ethyl and its metabolites in zebrafish

Jing

Zhai

et al. 2020

Chirality

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To investigate the impacts of the widely used chiral herbicide fenoxaprop‐ethyl (FE) on aquatic organisms, the enrichment, metabolism, acute toxicity, and oxidative stress of fenoxaprop‐ethyl and its main metabolites fenoxaprop (FA), ethyl‐2‐(4‐hydroxyphenoxy)propanoate (EHPP), 2‐(4‐hydroxyphenoxy)propanoic acid (HPPA), and 6‐chloro‐2,3‐dihydrobenzoxazol‐2‐one (CDHB) in zebrafish were studied. The enantioselectivity of fenoxaprop‐ethyl and its chiral metabolites was also determined. Fenoxaprop‐ethyl quickly degraded in zebrafish by aquatic exposure. FA, HPPA, and CDHB were the main metabolites that were enriched in the zebrafish. In the metabolism experiment, the half‐lives of the metabolites were 0.92–1.72 days in zebrafish. The R‐enantiomers of FA and HPPA were preferentially enriched and metabolized with enantiomeric fractions (EFs) of 0.65–0.85. According to the 96‐h acute toxicity, FA, HPPA, EHPP, and CDHB were less toxic to zebrafish than FE, following the order of FE > CDHB > EHPP > FA > HPPA. The S‐enantiomers of FE, FA, CDHB, and EHPP were more toxic than the R‐enantiomers. FE and its metabolites could significantly increase catalase (CAT) and superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content in gill and liver tissues, indicating their oxidative stress, and these effects were also enantioselective. This work could supply more information for evaluating the risks of fenoxaprop‐ethyl on aquatic organisms concerning their metabolites and enantiomers.

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“…It is reported that the enantiomeric abundance of methoxychlor metabolites depended on the relative catalytic activity of the hepatic P450 isoforms present . Different CYP enzymes resulted in different enantioselective behavior in rat microsomes of heptachlor . Further investigation is required to identify the relevant isoforms with P450 isoform‐specific inhibitors and/or recombinant enzymes.…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Metabolism and Interference on Tryptophan Metabolism of Myclobutanil in Rat Hepatocytes

et al. 2015

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Myclobutanil, (RS)-2-(4-chlorophenyl)-2-(1H-1, 2, 4-triazol-1-ylmethyl) hexanenitrile is a widely used triazole fungicide. In this study, enantioselective metabolism and cytotoxicity were investigated in rat hepatocytes by chiral HPLC-MS/MS and the methyl tetrazolium (MTT) assay, respectively. Furthermore, tryptophan metabolism disturbance in rat hepatocytes after myclobutanil exposure was also evaluated by target metabolomics method. The half-life (t1/2) of (+)-myclobutanil was 10.66 h, whereas that for (-)-myclobutanil was 15.07 h. Such results indicated that the metabolic process of myclobutanil in rat hepatocytes was enantioselective with an enrichment of (-)-myclobutanil. For the cytotoxicity research, the calculated EC50 (12 h) values for rac-myclobutanil, (+)- and (-)-myclobutanil were 123.65, 150.65 and 152.60 µM, respectively. The results of tryptophan metabolites profiling showed that the levels of kynurenine (KYN) and XA were both up-regulated compared to the control, suggesting the activation effect of the KYN pathway by myclobutanil and its enantiomers which may provide an important insight into its toxicity mechanism. The data presented here could be useful for the environmental hazard assessment of myclobutanil.

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Chlordane and Heptachlor Are Metabolized Enantioselectively by Rat Liver Microsomes

Cited by 24 publications

References 56 publications

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

The enantioselective enrichment, metabolism, and toxicity of fenoxaprop‐ethyl and its metabolites in zebrafish

Enantioselective Metabolism and Interference on Tryptophan Metabolism of Myclobutanil in Rat Hepatocytes

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