1132 Serum transaminase elevations alone lack specificity for detecting rare serious liver disease

Abstract

This chapter discusses the cellular machinery necessary for cytochrome P450 (CYP)1-3 gene induction is functional in human hepatocytes in long-term primary cultures (LTPC). First, thyrosine aminotransferase (TAT), a glucocorticoid receptor (GR)-driven gene, appears to be expressed constitutively in these cultures, suggesting a constitutive expression of GR. As this receptor controls the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) expression, it is not surprising that these two nuclear receptors are significantly expressed and functional, and this is finally consistent with CYP2B-2C and CYP3A gene induction. The constitutive expression of CYP2C9, a primary glucocorticoid responsive gene, is consistent with the constitutive expression of GR. LTPC provides an invaluable means to investigate the inducible expression and functional activity of human CYPs in their natural cellular environment. Indeed, it is remarkable that the protein and mRNA levels, as well as the enzyme activity of human CYP genes, including CYP1A2, CYP2C9, and CYP3A4, are maintained for at least 1 month in these cultures. However, further medium modifications are currently being tested to increase the expression of other CYP forms, including CYP2C19, CYP2D6, and CYP2E1.