Ethanol induces an aniline hydroxylase in chick embryo liver without inducing cytochrome P-450

1984 ◽  
Vol 12 (4) ◽  
pp. 686-686 ◽  
Author(s):  
FRANK BURNET ◽  
NIGEL DARBY
Keyword(s):  
Chick Embryo ◽  
Aniline Hydroxylase ◽  
Embryo Liver ◽  
Cytochrome P 450

Porphyrinogenic effects in chick embryo liver cell culture of chloramphenicol analogues that are mechanism-based inactivators of cytochrome P-450

1991 ◽  
Vol 69 (4) ◽  
pp. 526-530 ◽  
Author(s):  
R. P. Green-Thompson ◽  
D. S. Riddick ◽  
J. E. Mackie ◽  
G. S. Marks ◽  
J. R. Halpert
Keyword(s):  
Cell Culture ◽  
Chick Embryo ◽  
Rat Liver ◽  
Liver Cell ◽  
Prosthetic Group ◽  
Uroporphyrinogen Decarboxylase ◽  
Compound A ◽  
Liver Cell Culture ◽  
Embryo Liver ◽  
Cytochrome P 450

Structural analogues of chloramphenicol (CAP) cause mechanism-based inactivation of rat liver cytochrome P-450 (P450) either via protein acylation or destruction of the heme prosthetic group. The goal of the present work was to determine whether CAP analogues that cause loss of the P450 heme moiety also cause porphyrin accumulation in chick embryo liver cell culture. The porphyrin profiles produced by exposure of cells to CAP analogues (160 μM) were determined by high-performance liquid chromatography with fluorescence detection. Of three CAP analogues that do not cause loss of the heme moiety of rat liver P450IIB1, two dichloroacetamides were not porphyrinogenic. The third compound, a chlorofluoroacetamide, caused porphyrin accumulation. This result may be due to the presence of P450 isozymes in chick embryo hepatocytes, distinct from rat liver P450IIB1, that are susceptible to destruction by this analogue. Of four CAP analogues that inactivate rat liver P450IIB1 with concomitant heme loss, a dichloroacetamide and two chlorofluoroacetamides caused porphyrin accumulation. The remaining compound, a monochloroacetamide, was not porphyrinogenic, perhaps because the P450 apoprotein cannot be reconstituted with fresh heme drawn from the regulatory "free heme pool" following inactivation by this analogue. Alternatively, there may be no P450 isozyme in chick embryo liver cell culture that is susceptible to inactivation by this compound.Key words: cytochrome P-450, chloramphenicol, chick embryo hepatocyte, mechanism-based inactivation, uroporphyrinogen decarboxylase.

Inhibition of chick embryo hepatic uroporphyrinogen decarboxylase by components of xenobiotic-treated chick embryo hepatocytes in culture

1989 ◽  
Vol 67 (3) ◽  
pp. 246-249 ◽  
Author(s):  
C. A. James ◽  
G. S. Marks
Keyword(s):  
Chick Embryo ◽  
Protein Concentration ◽  
Enzyme Assay ◽  
Uroporphyrinogen Decarboxylase ◽  
Optimum Ph ◽  
Embryo Liver ◽  
Liver Homogenates ◽  
Previous Demonstration ◽  
Sodium Phenobarbital ◽  
Cytochrome P 450

Uroporphyrinogen decarboxylase (UROG-D) activity in the 10 000 g supernatant of 17-day-old chick embryo liver homogenates was determined by measuring the conversion of pentacarboxylporphyrinogen I to coproporphyrinogen I. The optimum pH of the enzyme was found to be approximately 6.0 and enzyme activity was found to be linear with protein concentrations ranging from 0.3 to 2.0 mg/mL. At a protein concentration of 1.2 mg/mL and pH 6.0, the activity was found to be linear for a reaction time of 50 min and to be approximately 10 pmol/(mg protein∙min). This enzyme assay was used to demonstrate that a UROG-D inhibitor, previously reported to accumulate in rodent liver, also accumulates in 3,3′4,4′-tretrachlorobiphenyl (TCBP) and sodium phenobarbital (PB) treated chick embryo hepatocytes in culture. This result accords with the previous demonstration of a TCBP- and PB-induced decrease in UROG-D activity in this system. Uroporphyrin accumulation in chick embryo hepatocyte culture is interpreted as resulting from a combination of two mechanisms, viz., inhibition of UROG-D activity and uroporphyrinogen oxidation to uroporphyrin catalyzed by a cytochrome P-450 isozyme.Key words: uroporphyrinogen decarboxylase, enzyme inhibition, chick embryo hepatocytes, tetrachlorobiphenyl, porphyria.

The 1986 Upjohn Award Lecture. Interaction of chemicals with hemoproteins: implications for the mechanism of action of porphyrinogenic drugs and nitroglycerin

1987 ◽  
Vol 65 (6) ◽  
pp. 1111-1119 ◽  
Author(s):  
Gerald S. Marks
Keyword(s):  
Chick Embryo ◽  
Guanylate Cyclase ◽  
Inhibitory Activity ◽  
Liver Cells ◽  
Enzymatic Reactions ◽  
Uroporphyrinogen Decarboxylase ◽  
Nitrite Ion ◽  
Catalytic Activation ◽  
Embryo Liver ◽  
Cytochrome P 450

The ferrochelatase inhibitory activity of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) was studied in chick embryo liver cells. The ferrochelatase inhibitory activity of the 4-butyl, 4-pentyl, and 4-hexyl analogues was considered to be due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of the corresponding N-alkylporphyrins. The relative ferrochelatase inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site. 3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) was shown to be a potent porphyrinogenic agent and to inhibit ferrochelatase in chick embryo liver cells. A related sydnone, 3-benzyl-4-phenylsydnone did not inhibit ferrochelatase activity. These results supported the idea that the porphyrinogenicity of TTMS was due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of N-vinylprotoporphyrin which inhibits ferrochelatase. Polychlorinated biphenyls, phenobarbital, nifedipine, and a large number of structurally different chemicals which are porphyrinogenic in chick embryo liver cells inhibit uroporphyrinogen decarboxylase by an unknown mechanism. Thus drug-induced porphyrin biosynthesis in chick embryo liver cell culture appears to be caused by inhibition of either ferrochelatase or uroporphyrinogen decarboxylase. The biotransformation of nitroglycerin by human red blood cells is due to a combination of a sulfhydryl-dependent enzymatic process and an interaction with reduced hemoglobin. Biotransformation of nitroglycerin was shown to occur only with the deoxy form of hemoglobin and to involve a two-electron denization, resulting in the oxidation of two molecules of heme iron (II) per mole of nitroglycerin biotransformed to glyceryl dinitrate and nitrite anion. Since nitroglycerin biotransformation appears to be involved in the mechanism of nitroglycerin-induced vasodilation, we have suggested the following hypothesis: biotransformation of nitroglycerin in vascular smooth muscle might occur by interaction of nitroglycerin with the iron (ferrous) of guanylate cyclase-bound heme. The nitrite ion formed may be converted via nitrous acid to nitric oxide. This in turn would combine with the heme moiety of guanylate cyclase to activate the enzyme and through a series of enzymatic reactions cause vasodilation.

scholarly journals Evidence that in chick embryos destruction of hepatic microsomal cytochrome P-450 haem is a general mechanism of induction of δ-aminolaevulinate synthase by porphyria-causing drugs

1980 ◽  
Vol 190 (3) ◽  
pp. 519-526 ◽  
Author(s):  
L K Lim ◽  
G Srivastava ◽  
J D Brooker ◽  
B K May ◽  
W H Elliott
Keyword(s):  
Chick Embryo ◽  
Enzyme Induction ◽  
General Mechanism ◽  
Chick Embryos ◽  
In Ovo ◽  
Microsomal Cytochrome ◽  
Primary Mechanism ◽  
Embryo Liver ◽  
The Relationship ◽  
Cytochrome P 450

A variety of prophyrinogenic compounds were tested for their effect in ovo on chick-embryo liver microsomal cytochrome P-450 haem concentration and mitochondrial delta-aminolaevulinate synthase activity. With all drugs tested, there was a 30—50% decrease in cytochrome P-450 haem concentration within 1 h of treatment, and this was closely followed by an increase in delta-aminolaevulinate synthase activity. The relationship was independent of the extent of enzyme induction and is consistent with the proposal that drug-mediated destruction of cytochrome P-450 haem is the primary mechanism of induction of delta-aminolaevulinate synthase. After induction, synthesis of delta-aminolaevulinate synthase could be maintained by inhibiting further haem synthesis. These studies suggest that induction of porphyria is a combination of two distinct processes: (a) induction of delta-aminolaevulinate synthase synthesis by destruction of cytochrome P-450 haem and consequent depletion of cellular free haem; (b) maintenance of continued delta-aminolaevulinate synthase synthesis by preventing replenishment of cellular haem either by inhibiting haem synthesis and/or by promoting continuous removal of newly synthesized haem.

Comparison of the effects of 3-ethoxycarbonyl-1,4-dihydro-2,4-dimethylpyridine and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine on ferrochelatase activity and heme biosynthesis in chick embryo liver cells in culture

1986 ◽  
Vol 64 (4) ◽  
pp. 483-486
Author(s):  
G. S. Marks ◽  
D. T. Allen ◽  
E. P. Sutherland ◽  
S. A. McCluskey ◽  
R. A. Whitney
Keyword(s):  
Aqueous Solution ◽  
Chick Embryo ◽  
Liver Cells ◽  
Heme Biosynthesis ◽  
Cells In Culture ◽  
Embryo Liver ◽  
Cytochrome P 450 ◽  
Lowering Activity ◽  
Rapid Transformation

3-Ethoxycarbonyl-1,4-dihydro-2,4-dimethylpyridine (EDP) was shown to lack the ferrochelatase-lowering activity of 3,5-diemoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) in chick embryo liver cells in culture. This was attributed to the inability of EDP to cause destruction of the heme moiety of cytochrome P-450 with concomitant formation of N-methylprotoporphyrin IX. EDP was less potent as a porphyrinogenic agent than DDC and caused the accumulation of uroporphyrin, heptacarboxylic porphyrin, and coproporphyrin in contrast with DDC which caused primarily protoporphyrin to accumulate. The inactivity of EDP as a ferrochelatase-lowering agent and its low porphyrinogenic potency was explained, at least in part, by its rapid transformation in aqueous solution to other nondihydropyridine products. The two ethoxycarbonyl substituents of DDC are therefore essential for N-methylprotoporphyrin formation, ferrochelatase-lowering activity, and optimal porphyrin-inducing activity.

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