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Reactive oxygen species-related induction of multidrug resistance-associated protein 2 expression in primary hepatocytes exposed to sulforaphane.

Abstract：

:Expression of multidrug resistance-associated protein 2 (MRP2), an efflux pump contributing to biliary secretion of xenobiotics, was investigated in primary rat and human hepatocytes exposed to sulforaphane, a naturally-occurring chemopreventive agent. Northern blot indicated that sulforaphane increased MRP2 mRNA levels in primary rat hepatocytes; it also induced expression of drug metabolizing enzymes such as glutathione S-transferase A1/2 isoforms and NAD(P)H:quinone oxidoreductase in a dose-response and time-course manner similar to that observed for the upregulation of MRP2 transcripts. This sulforaphane-related increase of MRP2 mRNAs paralleled increased expression of 190 kD MRP2 protein as assessed by Western blotting; it was fully abolished by the transcription inhibitor actinomycin D. MRP2 induction was associated with increased cellular production of reactive oxygen species (ROS) and addition of dimethyl sulfoxide, that reduced sulforaphane-related formation of ROS, and also decreased MRP2 mRNA levels in sulforaphane-treated primary rat hepatocytes; this suggests that sulforaphane-mediated production of ROS may contribute to MRP2 induction. This link between ROS and MRP2 regulation was further supported by the increase of MRP2 expression occurring in response to t-butylhydroquinone, known to regulate drug metabolizing enzymes through ROS formation. In addition to rat cells, primary human hepatocytes exposed to sulforaphane also displayed induced MRP2 expression evidenced at both mRNA and protein levels. All these observations strongly support the conclusion that the export pump MRP2 can be classified among the detoxifying proteins that are regulated by sulforaphane and that are thought to contribute, at least in part, to its anticarcinogenic properties.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Payen L,Courtois A,Loewert M,Guillouzo A,Fardel O

doi

10.1006/bbrc.2001.4531

subject

Has Abstract

pub_date

2001-03-23 00:00:00

pages

257-63

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(01)94531-0

journal_volume

282

pub_type

杂志文章

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