Is CYP1B1 involved in the metabolism of dioxins in the pig?

Molcan, Tomasz; Świgońska, Sylwia; Nynca, Anna; Sadowska, Agnieszka; Ruszkowska, Monika; Orlowska, Karina; Ciereszko, Renata E.

doi:10.1016/j.bbagen.2018.09.024

Cited by 3 publications

(11 citation statements)

References 70 publications

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“…e ., 1OH-TCDD (-24.415±0.050 kcal·mol −1 ) and 2OH-TCDD (-15.324±0.043 kcal·mol −1 ) showed higher affinity to the pCYP1A2 active site than TCDD. The pCYP1A2 demonstrated higher affinity towards DiCDD and TCDD in comparison to other members of pCYP1 enzymes [ 12 , 19 ] ( S3 Table ).…”

Section: Resultsmentioning

confidence: 99%

“…The extremely high toxicity of TCDD results from the occurence of chlorine atoms in all lateral positions and is accompanied by the highest resistance to biodegradation [ 9 , 10 ] (. In contrast, 2,7-dichlorodibenzo- p -dioxin (DiCDD), less toxic than TCDD and containing unsubstituted lateral positions, appears to be effectively metabolized [ 11 , 12 ]. TCDD’s high resistance to biodegradation results in its accumulation in adipose tissue and hence is, at least partially, responsible for its adverse effects exerted on living organisms [ 10 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…The detoxification process starts with reactions of hydroxylation occurring in heme-containing active site of the enzyme [ 8 , 15 , 17 , 18 ]. In our previous studies we analyzed the potential of pig CYP1A1 (pCYP1A; [ 12 ]) and CYP1B1 [ 19 ] to hydroxylate dioxins differing in toxicity and biodegradability. We have reported that TCDD, but not DiCDD, was not effectively metabolized by pCYP1A1 in pigs mainly due to the specific behavior of substrate channels leading into the active site of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…We have reported that TCDD, but not DiCDD, was not effectively metabolized by pCYP1A1 in pigs mainly due to the specific behavior of substrate channels leading into the active site of the enzyme. In silico analysis demonstrated that TCDD, upon its binding by CYP1A1, is not able to leave the enzyme’s active site because of the closure of the access channels [ 12 ]. Similar analysis performed for pig CYP1B1 demonstrated a smaller distance between heme oxygen and the nearest TCDD carbon atom, reflecting the higher hydroxylating potential of pig CYP1B1 than CYP1A1 [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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The involvement of CYP1A2 in biodegradation of dioxins in pigs

et al. 2022

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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the most harmful chemicals showing resistance to biodegradation. The majority of TCDD effects is mediated by the aryl hydrocarbon receptor (AhR) pathway. TCDD binding to AhR results in the activation of cytochrome P450 enzymes (CYP1A1, CYP1A2, CYP1B1) involved in dioxin biodegradation. The goal of the study was to explore the potential role of CYP1A2 in the metabolism of TCDD. We investigated a molecular structure of CYP1A2 and the binding selectivity and affinity between the pig CYP1A2 and: 1/ DiCDD or TCDD (dioxins differing in toxicity and biodegradability) or 2/ their selected metabolites. pCYP1A2 demonstrated higher affinity towards DiCDD and TCDD than other pCYP1 enzymes. All dioxin-pCYP1A2 complexes were found to be stabilized by hydrophobic interactions. The calculated distances between the heme oxygen and the dioxin carbon nearest to the oxygen, reflecting the hydroxylating potential of CYP1A2, were higher than in other pCYP1 enzymes. The distances between the heme iron and the nearest dioxin carbon exceeded 5 Å, a distance sufficient to allow the metabolites to leave the active site. However, the molecular dynamics simulations revealed that two access channels of CYP1A2 were closed upon binding the majority of the examined dioxins. Moreover, the binding of dioxin metabolites did not promote opening of channel S–an exit for hydroxylated products. It appears that the undesired changes in the behavior of access channels prevail over the hydroxylating potential of CYP1A2 towards TCDD and the favorable distances, ultimately trapping the metabolites at the enzyme’s active site.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The involvement of CYP1A2 in biodegradation of dioxins in pigs

et al. 2022

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“…Dioxins are permanent environmental pollutants that pose a potential risk to human health [1]. Among all dioxin compounds, TCDD is a highly toxic environmental contaminant [2].…”

Section: Introductionmentioning

confidence: 99%

Sıçanlarda 2,3,7,8-Tetraklorodibenzo-P-Dioksin (TCDD) 'nin Neden Olduğu Hepatoksisite ve Nefrotoksisite Üzerine Protokateşik Asitin (PCA) Rolü

Savcı

Özdemır

2020

Düzce Üniversitesi Bilim Ve Teknoloji Dergisi

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It is known that TCDD, one of the most toxic dioxin compounds, causes oxidative damage by forming free radical in human and animal tissues. In this study, the protective effect of PCA, an important phenolic compound, was examined in rat kidney and liver tissues with TCDD-induced toxicity. For this purpose, 28 Wistar Albino rats (3-4 months old and weighing 280-310 g) were used. Rats were randomly divided into 4 equal groups (control, TCDD, PCA and TCDD+PCA). TCDD and PCA were dissolved in corn oil at doses of 2 µg/kg and 100 mg/kg, respectively. Subsequently, the substances were administered to the rats by oral gavage for 45 days. The test results showed that in both kidney and liver tissues, TCDD increased the level of malondialdehyde (MDA) but inhibited the level of glutathione (GSH) and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). PCA administration was found to increase the enzyme activities and GSH levels, whereas it decreased the TCDD and MDA levels. In conclusion, it was observed that PCA decreased the TCDD-induced lipid peroxidation, increasing the antioxidant activity. Therefore, it might be suggested that PCA is a potential reducing agent for the toxicity caused by TCDD. Sıçanlarda 2,3,7,8-Tetraklorodibenzo-P-Dioksin (TCDD) 'nin Neden Olduğu Hepatoksisite ve Nefrotoksisite Üzerine Protokateşik Asitin (PCA) Rolü ÖZET En toksik dioksin bileşiklerinden biri olan TCDD'nin insan ve hayvan dokularında serbest radikal oluşturarak oksidatif hasara neden olduğu bilinmektedir. Bu çalışmada, TCDD tarafından toksisite oluşturulan sıçan karaciğeri ve böbreğinde önemli bir fenolik bileşik olan PCA'nın koruyucu etkileri araştırıldı. Bu amaçla 28 adet Wistar Albino cinsi sıçanlar (3-4 aylık ve 280-310 g ağırlığında) kullanıldı. Sıçanlar kontrol, TCDD, PCA ve TCDD + PCA olmak üzere rastgele 4 eşit gruba ayrıldı. TCDD ve PCA mısır yağı içinde çözüldü ve sırasıyla 2 µg / kg ve 100 mg / kg dozunda 45 gün boyunca gavaj yolu ile sıçanlara uygulandı. Çalışmanın sonunda TCDD'nin malondialdehit (MDA) seviyesini arttırdığı, ancak glutatyon (GSH) seviyesini ve süperoksit dismutaz (SOD), katalaz (CAT) ve glutatyon peroksidaz (GSH Px) aktivitelerini azalttığı gözlendi. PCA uygulamasının TCDD'nin aksine enzim aktivitelerini ve GSH seviyelerini arttırdığı ve MDA seviyelerini düşürdüğü tespit edildi. Sonuç olarak, PCA'nın TCDD'nin neden olduğu lipid peroksidasyonunu azalttığı ve antioksidan aktivitesini desteklediği görülmüştür. Bu nedenle PCA'nın, TCDD'nin neden olduğu toksisiteye karşı potansiyel bir indirgeyici madde olduğu öne sürülebilir.

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Transgenerational Transmission of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Effects in Human Granulosa Cells: The Role of MicroRNAs

Gaspari,

Haouzi,

Gennetier

et al. 2024

IJMS

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Endocrine-disrupting chemicals (EDCs) might contribute to the increase in female-specific cancers in Western countries. 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) is considered the “prototypical toxicant” to study EDCs’ effects on reproductive health. Epigenetic regulation by small noncoding RNAs (sncRNAs), such as microRNAs (miRNA), is crucial for controlling cancer development. The aim of this study was to analyze transcriptional activity and sncRNA expression changes in the KGN cell line after acute (3 h) and chronic (72 h) exposure to 10 nM TCDD in order to determine whether sncRNAs’ deregulation may contribute to transmitting TCDD effects to the subsequent cell generations (day 9 and day 14 after chronic exposure). Using Affymetrix GeneChip miRNA 4.0 arrays, 109 sncRNAs were found to be differentially expressed (fold change < −2 or >2; p-value < 0.05) between cells exposed or not (control) to TCDD for 3 h and 72 h and on day 9 and day 14 after chronic exposure. Ingenuity Pathway Analysis predicted that following the acute and chronic exposure of KGN cells, sncRNAs linked to cellular development, growth and proliferation were downregulated, and those linked to cancer promotion were upregulated on day 9 and day 14. These results indicated that TCDD-induced sncRNA dysregulation may have transgenerational cancer-promoting effects.

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Is CYP1B1 involved in the metabolism of dioxins in the pig?

Cited by 3 publications

References 70 publications

The involvement of CYP1A2 in biodegradation of dioxins in pigs

The involvement of CYP1A2 in biodegradation of dioxins in pigs

Sıçanlarda 2,3,7,8-Tetraklorodibenzo-P-Dioksin (TCDD) 'nin Neden Olduğu Hepatoksisite ve Nefrotoksisite Üzerine Protokateşik Asitin (PCA) Rolü

Transgenerational Transmission of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Effects in Human Granulosa Cells: The Role of MicroRNAs

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