Journal
ARCHIVES OF TOXICOLOGY
Volume 90, Issue 9, Pages 2261-2273Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-015-1593-7
Keywords
Benzo[a]pyrene; Inflammation; beta-Glucuronidase; Cytochrome P450 1A1; Carcinogen metabolism; IGF2R; DNA adducts
Categories
Funding
- Chinese Scholarship Council [CSC201307720049]
- Cancer Research UK [C313/A14329]
- National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Health Impact of Environmental Hazards at King's College London
- Public Health England (PHE)
- Cancer Research UK [14329] Funding Source: researchfish
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Neutrophils infiltrate tissues during inflammation, and when activated, they release beta-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular beta-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 beta-glucuronidase. beta-Glucuronidase reduced B[a] P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on beta-glucuronidase activity, because the inhibitor D-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of beta-glucuronidase. On the other hand, the inhibitory effect of beta-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for beta-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of beta-glucuronidase. Extracellular beta-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P-DNA adducts. Interestingly, at 24 h of exposure, beta-glucuronidase significantly enhanced CYP expression, probably because beta-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 beta-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 beta-glucuronidase. Overall, these data show that beta-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels.
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