EXTENT AND CHARACTER OF PHENOBARBITAL-MEDIATED CHANGES IN GENE-EXPRESSION IN THE LIVER

Phenobarbital elicits pleiotropic effects in the liver, including indu ction of enzymes involved in xenobiotic metabolism. The spectrum of th is response was analyzed by differential display of a large population (similar to 7500) of mRNAs in chicken embryo liver treated in vivo wi th phenobarbital. We identified 29 cDNA fragments that reproducibly an d significantly changed in intensity after a 48-hr in ovo treatment. E ighteen of these (62%) were increased, whereas 11 (38%) were decreased . Twenty strongly regulated cDNA fragments were subcloned and further analyzed. Nucleotide sequence analysis revealed three types of genes: (a) those previously described to be regulated by phenobarbital, inclu ding CYP2H1, glutathione S-transferase, and uridine diphosphate-glucur onosyltransferase; (b) genes reported herein for the first time to be regulated by phenobarbital, including fibrinogen beta-chain and gamma- chain, retinal glutamine synthetase, apolipoprotein B, two gene produc ts with homologies to elongation factor 16 and complement factor H, re spectively, and (c) several novel genes with hitherto unknown function s. If these data are extrapolated to the entire population of mRNAs of a liver cell, phenobarbital seems to significantly modulate the expre ssion of more than 50 different genes. Our results also demonstrate th at a large fraction of genes is negatively regulated by drug treatment .