Inhibition of uroporphyrinogen decarboxylase by 3,3′,4,4′-tetrachlorobiphenyl in chick embryo liver cell culture

1983 ◽  
Vol 61 (1) ◽  
pp. 105-108 ◽  
Author(s):  
M. G. Swain ◽  
S. B. Follows ◽  
G. S. Marks
Keyword(s):  
Cell Culture ◽  
High Pressure ◽  
Chick Embryo ◽  
Liver Cell ◽  
Liver Cells ◽  
Significant Inhibition ◽  
The Other ◽  
Decarboxylase Activity ◽  
Uroporphyrinogen Decarboxylase ◽  
Embryo Liver

An assay was developed to measure uroporphyrinogen decarboxylase activity in 17-day-old chick embryo liver cells in culture. Decarboxylation products arising from the action of uroporphyrinogen decarboxylase upon uroporphyrinogen III were quantitated using high-pressure liquid chromatography. 3,3′,4,4′-Tetrachlorobiphenyl (TCBP) was added to chick embryo liver cells and 24 h later the uroporphyrinogen decarboxylase activity in the ceils was measured; a significant inhibition was found. On the other hand, when TCBP was added directly to the crude uroporphyrinogen decarboxylase enzyme no inhibition was noted. The inhibition of uroporphyrinogen decarboxylase observed in this study explains the accumulation of uroporphyrin and heptacarboxylic porphyrin in chick embryo liver cell cultures treated with TCBP.

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.

Effects of porphyrin-inducing drugs on ferrochelatase activity in isolated mouse hepatocytes

1981 ◽  
Vol 59 (11) ◽  
pp. 1155-1158 ◽  
Author(s):  
Susan P. C. Cole ◽  
Thomas E. Massey ◽  
Gerald S. Marks ◽  
William J. Racz
Keyword(s):  
Cell Culture ◽  
Chick Embryo ◽  
Liver Cell ◽  
Mouse Hepatocyte ◽  
Liver Cell Culture ◽  
Embryo Liver ◽  
Mouse Hepatocytes ◽  
The Difference ◽  
Hepatocyte Suspension

The effects of several concentrations of griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) on ferrochelatase activity in suspensions of isolated mouse hepatocytes were examined. In agreement with previous findings in the intact chick embryo liver and chick embryo liver cell culture, DDC, but not griseofulvin, inhibited the enzyme in the isolated mouse hepatocyte suspension. These results indicate that the difference between the effects of griseofulvin on hepatic ferrochelatase in rodents in vivo (inhibition), the intact chick embryo (no effect), and the chick embryo liver cell culture (no effect) cannot be attributed solely to species differences.

A comparison of the porphyrin-inducing activity of barbiturates and benzodiazepines in chick embryo liver cells

1980 ◽  
Vol 58 (8) ◽  
pp. 991-995 ◽  
Author(s):  
S. Zimmer ◽  
H. Taub ◽  
G. S. Marks
Keyword(s):  
Cell Culture ◽  
Chick Embryo ◽  
Liver Cell ◽  
Aminolevulinic Acid ◽  
Synthetase Activity ◽  
Great Caution ◽  
Test Systems ◽  
Embryo Liver ◽  
Ala Synthetase ◽  
Hypnotic Dose

Five benzodiazepines, flurazepam, nitrazepam, diazepam, oxazepam, and chlordiazepoxide, have been tested for porphyrin-inducing activity in chick embryo liver cell culture and for δ-aminolevulinic acid (ALA) synthetase inducing activity in the 17-day-old chick embryo. Flurazepam and nitrazepam were found to have considerably lower potency than secobarbital whereas diazepam, oxazepam, and chlordiazepoxide were less potent than phenobarbital in these test systems. The following conclusions were arrived at. (1) A hypnotic dose of flurazepam or nitrazepam would be less likely than a comparable dose of secobarbital to increase ALA synthetase activity in a patient with hereditary hepatic porphyria. (2) A sedative dose of diazepam, oxazepam, or chlordiazepoxide would be less likely than a comparable dose of phenobarbital to increase ALA synthetase activity in a patient with hereditary hepatic porphyria. (3) The benzodiazepines, although apparently less likely to precipitate an attack than barbiturates, should be used with great caution in porphyria patients.

Inhibition of ferrochelatase by N-methylprotoporphyrin IX is not accompanied by δ-aminolevulinic acid synthetase induction in chick embryo liver cell culture

1982 ◽  
Vol 60 (2) ◽  
pp. 212-215 ◽  
Author(s):  
Susan P. C. Cole ◽  
Gerald S. Marks ◽  
Paul R. Oritz de Montellano ◽  
Kent L. Kunze
Keyword(s):  
Cell Culture ◽  
Chick Embryo ◽  
Liver Cell ◽  
Aminolevulinic Acid ◽  
Synthetase Activity ◽  
Liver Cell Culture ◽  
Embryo Liver ◽  
Ala Synthetase

N-Methylprotoporphyrin has been shown to markedly inhibit ferrochelatase activity in chick embryo liver cell culture without inducing δ-aminoievulinic acid (ALA) synthetase activity. This result supports the idea that the effects of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) on ALA synthetase activity and ferrochelatase activity are dissociated and that inhibition of ferrochelatase alone is not sufficient to cause induction of ALA synthetase. We conclude that the porphyrinogenic activity of DDC can be explained only in part by the actions of N-methylprotoporphyrin.

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 Studies of the influence of chloro-substituent sites and conformational energy in polychlorinated biphenyls on uroporphyrin formation in chick-embryo liver cell cultures

1986 ◽  
Vol 235 (1) ◽  
pp. 291-296 ◽  
Author(s):  
S Sassa ◽  
O Sugita ◽  
N Ohnuma ◽  
S Imajo ◽  
T Okumura ◽  
...  
Keyword(s):  
Chick Embryo ◽  
Polychlorinated Biphenyls ◽  
Phenyl Ring ◽  
Conformational Energy ◽  
Dimensional Structure ◽  
Molecular Orbital Calculations ◽  
Decarboxylase Activity ◽  
Uroporphyrinogen Decarboxylase ◽  
Halogen Atoms ◽  
Embryo Liver

Treatment of cultured chick-embryo liver cells with polychlorinated biphenyls (PCB) results in decreased uroporphyrinogen decarboxylase activity and increased uroporphyrin accumulation. In the present study we examined the effect of the chloro- or bromo-substituent sites in biphenyls (BP) on uroporphyrin accumulation in cultured hepatocytes and the three-dimensional structure of these congeners determined by molecular orbital calculations using a MNDO (‘modified neglect of diatomic overlap’) method. Among 20 congeners examined, those which were effective in stimulating porphyrin accumulation contained at least two Cl or Br atoms at the lateral adjacent positions in each phenyl ring, e.g. 3,4,3′,4′-tetrachloro-, 2,4,3′,4′-tetrachloro-, 3,4,5,3′,4′,5′-hexachloro- and 3,4,5,3′,4′,5′-hexabromobiphenyl, whereas those which contained less than two halogen atoms or more than three halogen atoms in each phenyl ring or those which contained halogen atoms at 2,2′-positions were not effective. On the basis of the conformational energy (delta E, difference from the most stable conformational energy), which is calculated as a function of the dihedral angle (theta) between the two phenyl rings, biphenyl congeners can be classified into four groups with different conformations. The conformation of active PCB was relatively flexible, whereas inactive species had a rigidly angulated conformation. Furthermore, the calculated probability of the conformation distribution for each congener indicated that the probability of co-planarity was higher for active biphenyls than for inactive congeners. These structural characteristics suggest the significance of both the chloro-substituent sites and the conformational energy reflecting the phenyl-ring twist angles in determining the inhibitory effect of PCB on uroporphyrinogen decarboxylase activity.

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