The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages.

doi:10.1093/toxsci/kfp044

Paper

The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages.

Published May 1, 2009 · Manabu Matsunawa, Y. Amano, Kaori Endo

Toxicological sciences : an official journal of the Society of Toxicology

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88

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3

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Abstract

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon produced by cigarette combustion, is implicated as a causative agent in smoking-related cancer and atherosclerosis. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a potent ligand for the nuclear receptor vitamin D receptor (VDR), has been shown to decrease the risk of osteoporosis, some types of cancer and cardiovascular disease, suggesting an opposing effect of vitamin D3 to cigarette smoking. In this study, we investigated the effects of BaP on the vitamin D3 signaling pathway. BaP effectively enhanced the 1,25(OH)2D3-dependent induction of cytochrome P450 24A1 (CYP24A1) in human monocyte/macrophage-derived THP-1 cells and breast cancer MCF-7 cells. BaP combination was less or not effective on mRNA expression of CD14, arachidonate 5-lipoxygenase, and cathelicidin antimicrobial peptide in THP-1 cells. BaP also increased the expression of CYP24A1 induced by a non-vitamin D VDR ligand, lithocholic acid acetate. Another aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, enhanced CYP24A1 expression by 1,25(OH)2D3 in THP-1 cells. Treatment of cells with an AhR antagonist and a protein synthesis inhibitor inhibited the enhancing effect of BaP on CYP24A1 induction, indicating that the effects of BaP are mediated by AhR activation and de novo protein synthesis. BaP pretreatment increased 1,25(OH)2D3-dependent recruitment of VDR and retinoid X receptor to the CYP24A1 promoter. Analysis of 1,25(OH)2D3 metabolism showed that BaP enhanced the hydroxylation of 1,25(OH)2D3 by CYP24A1 in THP-1 cells. Thus, AhR activation by BaP stimulates vitamin D3 catabolism. Modulation of vitamin D signaling by AhR may represent a mechanism underlying cigarette smoking-related diseases.

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Study Snapshot

Benzo[a]pyrene activates the aryl hydrocarbon receptor, potentially influencing vitamin D3 metabolism and contributing to smoking-related diseases.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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The aryl hydrocarbon receptor activator benzo[a]pyrene enhances vitamin D3 catabolism in macrophages.

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References

Inhibition of aryl hydrocarbon receptor transactivation and DNA adduct formation by CYP1 isoform-selective metabolic deactivation of benzo[a]pyrene.

CYP1A1 and CYP1B1 enzymes play a role in detoxifying benzo[a]pyrene by suppressing DNA adduct formation and activating the aryl hydrocarbon receptor.

Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia Published, JLR Papers in Press, January 7, 2008.

Lithocholic acid derivatives, such as LCA acetate and LCA propionate, can effectively activate the vitamin D receptor without causing hypercalcemia, making them potential therapeutic agents for immune disorders, microbial infections, and malignancies.

Vitamin D deficiency as a risk factor for osteoporotic fractures.

Low serum 25-hydroxyvitamin D levels are associated with an increased fracture risk in individuals aged 65-75 years, possibly due to high calcium intake in the Netherlands.

Vitamin D Deficiency and Risk of Cardiovascular Disease

Vitamin D deficiency is associated with an increased risk of developing cardiovascular disease.

Lifestyle-related factors and environmental agents causing cancer: an overview.

Environmental factors, such as microorganisms, radiations, and xenochemicals, play a more significant role in cancer genesis than previously thought, with the risk attributable to these factors being higher than previously believed.

Citations

Therapeutic Potential of Nutritional Aryl Hydrocarbon Receptor Ligands in Gut-Related Inflammation and Diseases

Nutritional aryl hydrocarbon receptor ligands show potential in modulating gut-related inflammation and diseases, offering potential treatments for critically ill patients.

Particulate matter 2.5 accelerates aging: Exploring cellular senescence and age-related diseases.

Exposure to PM 2.5 accelerates aging and contributes to age-related diseases, highlighting the need for personal and public health initiatives to reduce pollution and promote longevity.

Pathological Alterations in Lung and Liver of Male Mice Intoxicated with Benzo[a]pyrene: A time Dependent Study

Male mice exposed to varying doses of Benzo[a]pyrene show gradual lung hyperplastic proliferation and liver malignancy, leading to hepatocellular adenocarcinoma at 9 months.

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Novel strategies like natural senotherapeutics and mitochondrial transplantation may improve long-term outcomes in schizophrenia by addressing premature cellular/neuronal senescence and addressing early brain aging.

Regulation of Benzo[a]pyrene-Induced Hepatic Lipid Accumulation through CYP1B1-Induced mTOR-Mediated Lipophagy

CYP1B1-induced hepatic lipid accumulation is caused by mTOR and reduced lipophagy, offering new targets for understanding B[a]P-induced metabolic dysfunction-associated steatotic liver disease.