Inflammation alters the expression pattern of drug transporters during Caco‐2 cell stimulation and azoxymethane‐induced colon tumorigenesis

Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant tr...

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Published in:Journal of biochemical and molecular toxicology Vol. 38; no. 9; pp. e23815 - n/a
Main Authors: El‐Daly, Sherien M., Gouhar, Shaimaa A., Abdelrahman, Sahar S.
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01.09.2024
Subjects:
ABCB1
ABCC2
ABCG2
Animals
ATP Binding Cassette Transporter, Subfamily B - genetics
ATP Binding Cassette Transporter, Subfamily B - metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism
Azoxymethane
Azoxymethane - toxicity
Caco-2 Cells
Carcinogenesis - chemically induced
Carcinogenesis - metabolism
Cell Transformation, Neoplastic - chemically induced
Cell Transformation, Neoplastic - metabolism
Colitis
Colon
Colonic Neoplasms - chemically induced
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Colorectal cancer
drug transporters
Humans
Immunohistochemistry
Inflammation
Inflammation - chemically induced
Inflammation - metabolism
Inflammation - pathology
Interleukin 6
Interleukin-6 - metabolism
Male
Mice
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins - metabolism
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - metabolism
Tumorigenesis
drug transporters
ABCB1
ABCC2
colitis
inflammation
ABCG2
ISSN:1095-6670, 1099-0461, 1099-0461
Online Access:Get full text
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Summary:Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco‐2 cells to various inflammatory stimuli (IL‐1β, TNF‐α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL‐6 and NO production. Notably, inflamed Caco‐2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well‐established AOM/DSS mouse model known for its association with colitis‐driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL‐6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki‐67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki‐67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon. Acute and chronic inflammation alters the expression of specific drug transporters. Significant changes are detected in the expression of ABCB1, ABCG2, ABCC1, and ABCC2 in response to inflammation induced during the stepwise AOM/DSS tumorgenesis model. Drug transporters are crucial links between intestinal inflammation and tumorigenesis.
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ISSN:1095-6670
1099-0461
1099-0461
DOI:10.1002/jbt.23815