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

Abstract

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.

The effect of N‐methylprotoporphyrin and succinyl‐acetone on the regulation of heme biosynthesis in chicken hepatocytes in culture

“…The finding that two inhibitors of heme biosynthesis can enhance the stimulation of ALA-S caused by phenobarbital is compatible with the concept [4][5][6][7]29-321 that when the negative feedback control exercised by heme on ALA-S is diminished, the enzyme becomes more sensitive to stimulation by lipid-soluble drugs. This work also indicates that inhibition of heme bios~thesis can alone lead to a compensatory stimulation of ALA-S ( fig.…”

Cytochrome P450 regulation: the interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal

“…Although relatively small increases of ALAS1 activity are observed when either PB or an inhibitor of heme biosynthesis are given on their own, a marked potentiation of the ALAS1 induction is observed when these two treatments are combined, reflecting the individual contribution of two separate mechanisms (De Matteis & Gibbs, 1972; Maxwell & Meyer, 1976). In addition, drugs such as PB directly activate ALAS1 transcription, independent of their modulatory effects on the free heme pool (Hamilton et al, 1988; Ryan & Ades, 1989).…”

Enhanced Arsenite-Induced Hepatic Morphological and Biochemical Changes in Phenobarbital-Pretreated Rats

“…The total hepatic concentration of microsomal CYP450 was assessed by measuring its reduced-CO spectra (27). The metal chelatase activity was measured in the mitochondrial fraction by monitoring the incorporation of Co2+ into mesoporphyrin III (12). The 5-aminolevulinic acid dehydrase activity was assayed in the soluble cytosolic fraction by the formation of porphobilinogen, which forms a red-colored compound with p-dimethylaminobenzaldehyde (19).…”

“…-Liver electron micrographs.X 12,500 (see the Materials and Methods section). a) Control rats showing normal ultrastructure, b) arseniteonly treated rats showing changes in the rough endoplasmic reticulum changes, moderate vacuolation, some mitochondria degeneration, and an increased number of peroxisomes, c) PB-only treated rats showing myelin-like figures, degenerated mitochondria, and moderate loss of glycogen, and d) PB + As(III)-dosed rats showing ultrastructural changes resembling those caused by each chemical but considerably more severe.…”