Regulation of genes associated with drug metabolism.
Exposure of animals to foreign chemicals results in the induction of many enzymes. The mitochondrial enzyme 5-aminolaevulinate synthase (ALV-S) is induced to supply haem for cytochrome P-450 (P-450) enzymes, the key proteins in drug detoxification. The drugs phenobarbital and 2-allyl-2-isopropylacetamide (AIA), although structurally different, elevate levels of ALV-S and a specific class of P-450s, the phenobarbital-inducible P-450s. Synthesis of ALV-S is negatively controlled by the end-product haem and it is proposed that drugs induce P-450 apoprotein which sequesters haem. Studies at the mRNA level show that ALV-S and P-450 are drug induced in a highly tissue-specific fashion and that haem represses mRNA levels in all but erythroid tissues. In liver, drugs activate ALV-S gene transcription and haem represses, but this mechanism does not operate in erythroid cells. Studies on the drug-induction mechanism of phenobarbital-inducible P-450s in chick embryo liver show that increased mRNA levels result from P-450 gene activation together with a significant post-transcriptional mechanism.
Elliott
W H
WH
Adelaide University Centre for Gene Technology, Department of Biochemistry, University of Adelaide, South Australia.
May
B K
BK
Bawden
M J
MJ
Hansen
A J
AJ
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000502:Allylisopropylacetamide / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006418:Heme / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D010634:Phenobarbital / Q000493:pharmacokinetics*; D012333:RNA, Messenger; D051381:Rats; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D012333:RNA, Messenger; D000502:Allylisopropylacetamide; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital