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J. Biol. Chem., Vol. 279, Issue 14, 13953-13961, April 2, 2004

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Gene Expression Changes Associated with the Endoplasmic Reticulum Stress Response Induced by Microsomal Cytochrome P450 Overproduction^*

Elzbieta Szczesna-Skorupa, Ci-Di Chen¶, Hong Liu||, and Byron Kemper**

From the Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, the ^¶Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota 55455, and ^||Aventis Pharmaceuticals Inc., Bridgewater, New Jersey 08807

Induction of drug-metabolizing microsomal cytochromes P450 (P450s) results in a striking proliferation of the smooth endoplasmic reticulum (ER). Overexpression of P450s in yeast and cultured cells produces a similar response. The signals mediating this process are not known but probably involve signal transduction pathways involved in the unfolded protein response (UPR) or the ER overload response (EOR). We have examined the temporal response of specific genes in these pathways and genes globally to overexpression of P450 in cultured cells. Activity of NFB, an EOR component, was substantially increased by overexpression of full-length P450 2C2 or a chimera with the 28-amino acid signal anchor sequence of P450 2C2 in HepG2 cells, and the activation correlated temporally with the accumulation of P450 in the cells. In the UPR pathway, activation of the transcription factor XBP1 by IRE1 also correlated with the accumulation of P450 in the cells, and in contrast, maximum activation of the BiP/grp78 promoter preceded the accumulation. Differential effects of expression of P450 on apoptosis were observed in nonhepatic COS1 and hepatic HepG2 cells. In COS1 cells, apoptosis was induced, and this correlated with sustained activation of the pro-apoptotic JNK pathway, induction of CHOP, and an absence of the increased NFB activity. In HepG2 cells, JNK was only transiently activated, and CHOP expression was not induced. As assessed by DNA microarray analysis, up-regulation of signaling genes was predominant including those involved in anti-apoptosis and ER stress. These results suggest that both the EOR and UPR pathways are involved in the cellular response to induction of P450 expression and that in hepatic cells genes are also induced to block apoptosis, which may be a physiologically relevant response to prevent cell death during xenobiotic induced expression of P450 in the liver.

Received for publication, November 6, 2003 , and in revised form, January 7, 2004.

^* This work was supported by National Institutes of Health Grant GM35897, the Minnesota Lions Macular Degeration Center, and the Minnesota Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Tables III and IV.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: University of Illinois at Urbana-Champaign, 407 S. Goodwin Ave., Urbana, IL 61801. Tel.: 217-333-1146; E-mail: byronkem{at}life.uiuc.edu.

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