IN-SITU HYBRIDIZATION ANALYSIS OF HEPATIC CYTOCHROME-P450 2E1 MESSENGER-RIBONUCLEIC-ACID IN MICE - MODULATION OF EXPRESSION BY ACETONE

BACKGROUND: Cytochrome P450 2E1 is a distinct enzyme induced by divers e agents and notably by solvents including acetone. The P450 2E1 apopr otein is predominantly localized in the centrilobular region of the he patic lobule in the constitutive state and after induction with aceton e. In this study, we investigated the level and pattern of distributio n of the 2E1 mRNA within the hepatic lobule in control mice and in mic e exposed to acetone under acute and chronic conditions. EXPERIMENTAL DESIGN: Male CD-1 mice were administered acetone acutely (5 ml/kg) or chronically (1% in drinking water for 8 days). Cytochrome P450 2E1 mRN A was detected in liver tissues, using in situ hybridization with a H- 3-labeled RNA probe coupled with quantitative image analysis. RESULTS: Acetone exposure did not alter the distance spanning a central vein a nd an adjacent portal vein. In control mice, 2E1 mRNA transcripts were localized most abundantly in the centrilobular zone of the hepatic lo bule; intermediate levels were found in the midzonal region, and minim al levels were found in the periportal region. In acetone-treated mice , 2E1 mRNA expression within the hepatic lobule was significantly redu ced and was manifested, firstly, in a decreased hepatocyte population with high expression, as assessed by reduction of total acinar areas c ontaining 2E1 mRNA transcripts, and, secondly, in reduced 2E1 mRNA con tent within the hepatocytes. These alterations were observed to a sign ificantly greater extent in mice after chronic versus acute acetone ex posure. CONCLUSIONS: Our results showed that acetone exposure in mice results in both a reduction and a more restricted distribution of 2E1 mRNA within the hepatic lobule. Furthermore, these findings suggest th at 2E1 enzyme induction is associated with post-transcriptional events that are more marked after chronic than after acute exposure.