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Inflammation-associated extracellular β-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene.

Abstract：

:Neutrophils infiltrate tissues during inflammation, and when activated, they release β-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular β-glucuronidase changed the in vitro cellular response to the chemical carcinogen benzo(a)pyrene (B[a]P). For this we exposed human liver (HepG2) and lung (A549) cells to B[a]P in the presence or absence of β-glucuronidase. β-Glucuronidase reduced B[a]P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on β-glucuronidase activity, because the inhibitor D-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of β-glucuronidase. On the other hand, the inhibitory effect of β-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for β-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of β-glucuronidase. Extracellular β-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P-DNA adducts. Interestingly, at 24 h of exposure, β-glucuronidase significantly enhanced CYP expression, probably because β-glucuronidase de-glucuronidated B[a]P metabolites, which continued to trigger the aryl hydrocarbon receptor (Ah receptor) and induced expression of CYP1A1 (in both cell lines) and CYP1B1 (in A549 only). Consequently, significantly higher concentrations of B[a]P metabolites and DNA adducts were found in β-glucuronidase-treated cells at 24 h. DNA adduct levels peaked at 48 h in cells that were exposed to B[a]P and treated with β-glucuronidase. Overall, these data show that β-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Shi Q,Haenen GR,Maas L,Arlt VM,Spina D,Vasquez YR,Moonen E,Veith C,Van Schooten FJ,Godschalk RWL

doi

10.1007/s00204-015-1593-7

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

2261-2273

issue

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-015-1593-7

journal_volume

pub_type

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Inflammation-associated extracellular β-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene.