Journal Article

NO-donating aspirin induces phase II enzymes <i>in vitro</i> and <i>in vivo</i>

Jianjun Gao, Khosrow Kashfi, Xiaoping Liu and Basil Rigas

in Carcinogenesis

Volume 27, issue 4, pages 803-810
Published in print April 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi262
NO-donating aspirin induces phase II enzymes in vitro and in vivo

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Modulation of drug metabolizing enzymes, leading to facilitated elimination of carcinogens represents a successful strategy for cancer chemoprevention. Nitric oxide-donating aspirin (NO-ASA) is a promising agent for the prevention of colon and other cancers. We studied the effect of NO-ASA on drug metabolizing enzymes in HT-29 human colon adenocarcinoma and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Min mice treated with NO-ASA for 3 weeks. In these cell lines, NO-ASA induced the activity and expression of NAD(P)H:quinone oxireductase (NQO) and glutathione S-transferase (GST). Compared with untreated Min mice, NO-ASA increased in the liver the activity (nmol/min/mg; mean ± SEM for all) of NQO (85 ± 6 versus 128 ± 11, P<0.05) and GST (2560 ± 233 versus 4254 ± 608, P < 0.005) and also in the intestine but not in the kidney; the expression of NQO1 and GST P1-1 was also increased. NO-ASA had only a marginal effect on P450 1A1 and P450 2E1, two phase I enzymes. The release of NO from NO-ASA, determined with a selective microelectrode was paralleled by the induction of NQO1 and abrogated by NO scavengers; an exogenous NO donor also induced the expression of NQO1. NO-ASA induced concentration-dependently the translocation of Nrf2 into the nucleus as documented by immunofluorescence and immunoblotting; this paralleled the induction of NQO1 and GST P1-1. Thus NO-ASA induces phase II enzymes, at least in part, through the action of NO that it releases and by modulating the Keap1–Nrf2 pathway; this effect may be part of its mechanism of action against colon and other cancers.

Keywords: ARE, antioxidant response element; CDNB, 1-chloro-2,4-dinitrobenzene; CYP, cytochrome P450; DMSO, dimethyl sulfoxide; DTNB, 5,5′-dithiobis 2-nitrobenzoic acid; GST, glutathione S-transferase; NO-ASA, NO-donating aspirin; NO-NSAIDs, Nitric oxide-donating non-steroidal anti-inflammatory drugs; NQO, NAD(P)H:quinone oxireductase; PTIO, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; SNAP, S-nitroso-N-acetyl-penicillamine; UGT, UDP-glucuronyltransferase

Journal Article.  5226 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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