SUICIDAL DESTRUCTION OF CYTOCHROME-P-450 AND REDUCTION OF FERROCHELATASE ACTIVITY BY 3,5-DIETHOXYCARBONYL-1,4-DIHYDRO-2,4,6-TRIMETHYLPYRIDINE AND ITS ANALOGS IN CHICK-EMBRYO LIVER-CELLS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (4) , 459-465
Abstract
The ferrochelatase-reducing activity and cytochrome P-450- and heme-destructive effects of a variety of analogs of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. A group of DDC analogs was found in which an inability to reduce ferrochelatase activity corresponded with an inability to cause cytochrome P-450 and heme destruction. In a 2nd group of DDC analogs, the ability to reduce ferrochelatase activity corresponded with the ability to cause cytochrome P-450 and heme destruction. These observations support the idea that the protoporphyrin IX moiety of N-alkylprotoporphyrin IX originates from the heme moiety of cytochrome P-450. A 3rd group of DDC analogs caused cytochrome P-450 and heme destruction despite an inability to reduce ferrochelatase activity. With this 3rd group of DDC analogs, the heme moiety of cytochrome P-450 is likely degraded to products other than N-alkylporphyrins. The inability of several lipophilic DDC analogs [4-benzyl,4-isopropyl,4-cyclohexyl,4-(3-cyclohexenyl)] to reduce hepatic ferrochelatase activity may explain their low porphyrinogenicity. The pattern of porphyrin accumulation produced in response to 2 DDC analogs that did not inhibit ferrochelatase was investigated using high performance liquid chromatography. Coproporphyrin was the major porphyrin to accumulate in response to the 4-isopropyl analog and uro- and heptacarboxylic acid porphyrins in response to the 4-benzyl analog. These patterns of porphyrin accumulation are consistent with the inability of these analogs to inhibit ferrochelatase.