Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses

Milanowski, Bartłomiej; Lulek, Janina; Lehmler, Hans‐Joachim; Kania-Korwel, Izabela

doi:10.1016/j.envint.2009.10.007

Cited by 26 publications

(50 citation statements)

References 50 publications

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“…The mice is a notable exception, with E 1 -5-HO-PCB136 and E 1 -4-HO-PCB136 formed preferentially in vitro (Wu et al 2013a, Wu et al 2014). In agreement with this finding, mice display an enrichment of (+)-PCB 136 in all tissues and excreta (Kania-Korwel et al 2010, Kania-Korwel et al 2008a, Kania-Korwel et al 2007, Kania-Korwel et al 2008d, Milanowski et al 2010). …”

Section: Metabolism Of C-pcbs To Ho-pcbssupporting

confidence: 82%

“…It is possible that, in addition to passive diffusion, active transport processes play a role in the absorption of C-PCB in the gastrointestinal tract and, thus, contribute to the atropisomeric enrichment of C-PCBs observed in vivo ; however, animal studies do not support the hypothesis that PCBs are substrates for active transporters, such as multidrug resistance transporters (Milanowski et al 2010, Tampal et al 2003). It is more likely that atropselective metabolism at the site of PCB absorption contributes to the atropisomeric enrichment of C-PCBs.…”

Section: Absorption Of C-pcbsmentioning

confidence: 99%

“…Moreover, the atropisomeric enrichment of E 2 -PCB 95 in the in vitro metabolism experiments is consistent with the atropisomeric enrichment of PCB 95 observed in rats treated with an Aroclor 1254 mixture (Kania-Korwel et al 2006). Similarly, in vitro metabolism studies (Wu et al 2013a) accurately predict the direction of the atropisomeric enrichment of PCB 136 (Kania-Korwel et al 2010, Kania-Korwel et al 2008a, Kania-Korwel et al 2007, Kania-Korwel et al 2008d, Milanowski et al 2010) and PCB 95 (Kania-Korwel et al 2012, Kania-Korwel et al 2010, Milanowski et al 2010) in mice in vivo . Incubations with human CYP2B6 result in biotransformation of PCBs 45, 91 and 132; however, only the biotransformation of PCBs 45 and 132 is enantioselective.…”

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 99%

“…These excretion processes occur by passive diffusion and, therefore, are not atropselective. Although PCBs apparently are not substrates for active transporters, such as multidrug resistance transporters (Milanowski et al 2010, Tampal et al 2003), in in vivo studies, the possibility that atropselective active transport processes contribute to the excretion of C-PCBs cannot be completely ruled out. Moreover, it is currently unknown if active transporters are involved in the excretion of PCB metabolites.…”

Section: Excretion Of C-pcbs and Their Metabolitesmentioning

confidence: 99%

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Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

Kania-Korwel

Lehmler

2015

Environ Sci Pollut Res

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103

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Seventy eight out of the 209 possible polychlorinated biphenyl (PCB) congeners are chiral, nineteen of which exist under ambient conditions as stable rotational isomers that are non-superimposable mirror images of each other. These congeners (C-PCBs) represent up to 6% by weight of technical PCB mixtures and undergo considerable atropisomeric enrichment in wildlife, laboratory animals and humans. The objective of this review is to summarize our current knowledge of the processes involved in the absorption, metabolism and excretion of C-PCBs and their metabolites in laboratory animals and humans. C-PCBs are absorbed and excreted by passive diffusion, a process that, like other physicochemical processes, is inherently not atropselective. In mammals, metabolism by cytochrome P450 (P450) enzymes represents a major route of elimination for many C-PCBs. In vitro studies demonstrate that C-PCBs with a 2,3,6-trichlorosubstituion pattern in one phenyl ring are readily oxidized to hydroxylated PCB metabolites (HO-PCBs) by P450 enzymes, such as rat CYP2B1, human CYP2B6 and dog CYP2B11. The oxidation of C-PCBs is atropselective, thus resulting in a species and congener-dependent atropisomeric enrichment of C-PCBs and their metabolites. This atropisomeric enrichment of C-PCBs and their metabolites likely plays a poorly understood role in the atropselective toxicity of C-PCBs and, therefore, warrants further investigation.

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Section: Metabolism Of C-pcbs To Ho-pcbssupporting

confidence: 82%

Section: Absorption Of C-pcbsmentioning

confidence: 99%

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 99%

Section: Excretion Of C-pcbs and Their Metabolitesmentioning

confidence: 99%

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Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

Kania-Korwel

Lehmler

2015

Environ Sci Pollut Res

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103

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“…Because only four tissues and a limited number of PCB metabolites were quantified in the present study, it was not possible to obtain a complete mass balance of PCB 95. Adipose tissue, a well-documented storage tissue of PCBs, 32, 37, 41 accounted for approximately 0.24–0.27% of the total PCB 95 dose, which is considerably lower compared to earlier disposition studies with PCB 136 in mice. 33, 37, 41 All other tissues investigated accounted for only minute amounts of the total PCB 95 dose (< 0.05 % of the total dose).…”

Section: Discussionmentioning

confidence: 71%

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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Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

Dhakal

Gadupudi

Lehmler

et al. 2017

Environ Sci Pollut Res

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Polychlorinated biphenyls (PCBs), a group of 209 congeners that differ in the number and position of chlorines on the biphenyl ring, are anthropogenic chemicals that belong to the persistent organic pollutants (POPs). For many years, PCBs have been a topic of interest because of their biomagnification in the food chain and their environmental persistence. PCBs with fewer chlorine atoms, however, are less persistent and more susceptible to metabolic attack, giving rise to chemicals characterized by the addition of one or more hydroxyl groups to the chlorinated biphenyl skeleton, collectively known as hydroxylated PCBs (OH-PCBs). In animals and plants, this biotransformation of PCBs to OH-PCBs is primarily carried out by cytochrome P-450-dependent monooxygenases. One of the reasons for infrequent detection of lower chlorinated PCBs in serum and other biological matrices is their shorter half-lives, and their metabolic transformation, resulting in OH-PCBs or their conjugates, such as sulfates and glucuronides, or macromolecule adducts. Recent biomonitoring studies have reported the presence of OH-PCBs in human serum. The occurrence of OH-PCBs, the size of this group (there are 837 mono-hydroxyl PCBs alone), and their wide spectra of physical characteristics (pKa's and log P's ranging over 5 to 6 orders of magnitude) give rise to a multiplicity of biological effects. Among those are bioactivation to electrophilic metabolites that can form covalent adducts with DNA and other macromolecules, interference with hormonal signaling, inhibition of enzymes that regulate cellular concentrations of active hormones, and interference with the transport of hormones. This new information creates an urgent need for a new perspective on these often overlooked metabolites.

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Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses

Cited by 26 publications

References 50 publications

Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

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

Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

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