Haem synthesis from exogenous 5-aminolaevulinate in cultured chick-embryo hepatocytes. Effects of inducers of cytochromes P-450.
The effects of inducers of cytochrome P-450 on haem biosynthesis from 5-aminolaevulinate were examined by using cultured chick-embryo hepatocytes. Cultures treated with either 2-propyl-2-isopropylacetamide or 3-methylcholanthrene contained increased amounts of cytochrome P-450 and haem. After treatment for 3 h with 5-amino[4-14C]laevulinate, the relative amounts of radioactivity accumulating as haem corresponded to the relative amounts of total cellular haem, but not to increases in the amounts of cytochrome P-450. Treatment with 5-aminolaevulinate did not alter cellular haem or cytochrome P-450 concentrations in either control or drug-treated cultures. The mechanism of the enhanced accumulation of radioactivity in haem was investigated. Although 2-propyl-2-isopropylacetamide enhanced the uptake of 5-aminolaevulinate and increased the cellular concentration of porphobilinogen 1.5-fold, these changes did not account for the increases in haem radioactivity. The inducing drugs had no effect on the rates of degradation of radioactive haem, but appeared to enhance conversion of protoporphyrin into haem. This latter effect was shown by: (1) a decreased accumulation of protoporphyrin from 5-aminolaevulinate in cells treated with inducers, and (2) complete prevention of this decrease if the iron chelator desferrioxamine was present. We conclude that inducers of cytochrome P-450 may increase haem synthesis not only by increasing activity of 5-aminolaevulinate synthase, but also by increasing conversion of protoporphyrin into haem.
Shedlofsky
S I
SI
Veterans Administration Medical Center, Lexington, KY 40511.
Sinclair
P R
PR
Bonkovsky
H L
HL
Healey
J F
JF
Swim
A T
AT
Robinson
J M
JM
D000502:Allylisopropylacetamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000622:Aminolevulinic Acid / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003676:Deferoxamine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis*; D007982:Levulinic Acids / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology; D011162:Porphobilinogen / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism
D007982:Levulinic Acids; D011166:Porphyrins; D000502:Allylisopropylacetamide; D006418:Heme; D008748:Methylcholanthrene; C009072:propylisopropylacetamide; D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D003676:Deferoxamine