Tissue Organoid Cultures Metabolize Dietary Carcinogens Proficiently and Are Effective Models for DNA Adduct Formation

Overview

Journal Chem Res Toxicol

Publisher American Chemical Society

Specialty Toxicology

Date 2024 Jan 17

PMID 38232180

Authors

Angela L Caipa Garcia

Jill E Kucab

Halh Al-Serori

Rebekah S S Beck

Madjda Bellamri

Robert J Turesky

John D Groopman

Hayley E Francies

Mathew J Garnett

Meritxell Huch

Jarno Drost

Matthias Zilbauer

Volker M Arlt

David H Phillips

Affiliations

Soon will be listed here.

Abstract

Human tissue three-dimensional (3D) organoid cultures have the potential to reproduce the physiological properties and cellular architecture of the organs from which they are derived. The ability of organoid cultures derived from human stomach, liver, kidney, and colon to metabolically activate three dietary carcinogens, aflatoxin B (AFB), aristolochic acid I (AAI), and 2-amino-1-methyl-6-phenylimidazo[4,5-]pyridine (PhIP), was investigated. In each case, the response of a target tissue (liver for AFB; kidney for AAI; colon for PhIP) was compared with that of a nontarget tissue (gastric). After treatment cell viabilities were measured, DNA damage response (DDR) was determined by Western blotting for p-p53, p21, p-CHK2, and γ-H2AX, and DNA adduct formation was quantified by mass spectrometry. Induction of the key xenobiotic-metabolizing enzymes (XMEs) CYP1A1, CYP1A2, CYP3A4, and NQO1 was assessed by qRT-PCR. We found that organoids from different tissues can activate AAI, AFB, and PhIP. In some cases, this metabolic potential varied between tissues and between different cultures of the same tissue. Similarly, variations in the levels of expression of XMEs were observed. At comparable levels of cytotoxicity, organoids derived from tissues that are considered targets for these carcinogens had higher levels of adduct formation than a nontarget tissue.

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