Stimulation of liver 5-aminolaevulinate synthetase by drugs and its relevance to drug-induced accumulation of cytochrome P-450. Studies with phenylbutazone and 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
The relevance of the stimulation of 5-aminolaevulinate synthetase to the accumulation of cytochrome P-450 after administration of drugs was examined in rats treated with phenylbutazone and with 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine alone stimulated 5-aminolaevulinate synthetase without increasing the concentration of cytochrome P-450, whereas phenylbutazone alone increased the microsomal cytochrome P-450 without significantly affecting the activity of the enzyme. When the two drugs were given together both effects were found. It is concluded that if an increased amount of 5-aminolaevulinate and haem must be made to provide for the accumulation of cytochrome P-450, it need only be a small amount. It is also concluded from these findings that stimulation of the drug-metabolizing system on the one hand and marked enhancement of 5-aminolaevulinate synthetase activity and porphyria on the other are likely to result from different actions of the drugs. Evidence is presented suggesting that porphyrogenic drugs stimulate markedly the activity of 5-aminolaevulinate synthetase by lowering the concentration of haem in the liver, thereby decreasing the normal feedback control. With 3,5-diethoxycarbonyl-1,4-dihydrocollidine a rapid inhibition of mitochondrial ferrochelatase and of liver haem synthesis may be the primary mechanism involved.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D000818:Animals; D003580:Cytochromes / Q000378:metabolism*; D003998:Dicarboxylic Acids; D004790:Enzyme Induction; D004952:Esters; D006418:Heme / Q000096:biosynthesis; D007503:Iron Isotopes; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D010653:Phenylbutazone / Q000494:pharmacology*; D011164:Porphyrias / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats
D003580:Cytochromes; D003998:Dicarboxylic Acids; D004952:Esters; D007503:Iron Isotopes; D011725:Pyridines; D006418:Heme; D000624:5-Aminolevulinate Synthetase; D010653:Phenylbutazone