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.

Drug-Induced Porphyrin Biosynthesis—VIII. Investigation of the Importance of an Allyl Group for Activity in Substituted Acetamides

1973 ◽  
Vol 51 (11) ◽  
pp. 863-868 ◽  
Author(s):  
G. S. Marks ◽  
V. Krupa ◽  
M. W. Roomi
Keyword(s):  
Cell Culture ◽  
Chick Embryo ◽  
Liver Cell ◽  
Aminolevulinic Acid ◽  
Developmental Differences ◽  
Synthetase Activity ◽  
Drug Induced ◽  
Liver Cell Culture ◽  
Embryo Liver ◽  
Ala Synthetase

Allylisopropylacetamide (AIA) was found to be considerably more potent than propylisopropylacetamide (PIA) in inducing hepatic δ-aminolevulinic acid (ALA) synthetase activity and hepatic porphyrin accumulation in the 17-day-old chick embryo, chickens, and mice of the CBA/J strain. AIA and PIA were shown to be approximately equipotent in inducing ALA synthetase activity and porphyrin accumulation in chick embryo liver cell culture. It is likely that the unusual responsiveness of chick embryo liver cell culture to PIA is not due to species or developmental differences but to the large amount of PIA available to the cultured liver cells.

Drug-Induced Porphyrin Biosynthesis. X. Potentiation of Propanidid-Induced Elevation of δ-Aminolevulinic Acid Synthetase and Porphyrins in Chick Embryo Liver by the Carboxylesterase Inhibitor Bis-[p-nitrophenyl] Phosphate

1973 ◽  
Vol 51 (9) ◽  
pp. 700-704 ◽  
Author(s):  
Hillel Taub ◽  
G. S. Marks
Keyword(s):  
Chick Embryo ◽  
Aminolevulinic Acid ◽  
Ester Group ◽  
Synthetase Activity ◽  
Chick Embryos ◽  
Drug Induced ◽  
Duration Of Action ◽  
Nitrophenyl Phosphate ◽  
Embryo Liver ◽  
Ala Synthetase

Propanidid, an ultra short-acting non-barbiturate anesthetic containing an ester group, induces δ-aminolevulinic acid (ALA)-synthetase and porphyrin accumulation in 17-day-old chick embryo liver. The potency and duration of action of propanidid in inducing ALA-synthetase activity and porphyrin accumulation was markedly increased when administered to chick embryos which had been pretreated with bis-[p-nitrophenyl] phosphate, an inhibitor of liver carboxylesterase.

Drug-Induced Porphyrin Biosynthesis—XII. Levels of Cytochrome P-450 in Chick Embryo Liver following Administration of Allylisopropylacetamide and Propylisopropylacetamide

1974 ◽  
Vol 52 (4) ◽  
pp. 891-895 ◽  
Author(s):  
V. Krupa ◽  
J. C. Creighton ◽  
M. Freeman ◽  
G. S. Marks
Keyword(s):  
Chick Embryo ◽  
Aminolevulinic Acid ◽  
The Other ◽  
Synthetase Activity ◽  
Drug Induced ◽  
Liver Cytochrome ◽  
Time Period ◽  
Embryo Liver ◽  
Ala Synthetase ◽  
Cytochrome P 450

Allylisopropylacetamide caused a decrease in the level of chick embryo liver cytochrome P-450 1 h after administration, followed by an elevation above control levels at a later time period. Propylisopropylacetamide on the other hand did not produce an early decrease in cytochrome P-450 but produced an elevation of cytochrome P-450 at a later time period. Since propylisopropylacetamide is an inducer of δ-aminolevulinic acid synthetase activity and porphyrin accumulation in chick embryo liver, it was concluded that a loss of cytochrome P-450 is not a prerequisite for ALA-synthetase induction as is thought to be the case in rats.

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.

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.

Drug metabolism in cell culture. II. Studies on the metabolic route of DDC analogues

1977 ◽  
Vol 55 (3) ◽  
pp. 552-559 ◽  
Author(s):  
William J. Racz ◽  
Lynette Hunter ◽  
Richard G. F. Wanless ◽  
Miriam V. McDonald ◽  
Joyce A. Moffat
Keyword(s):  
Cell Culture ◽  
Half Life ◽  
Aminolevulinic Acid ◽  
Piperonyl Butoxide ◽  
Metabolic Route ◽  
Nitrophenyl Phosphate ◽  
Intact Embryo ◽  
Embryo Liver ◽  
Ala Synthetase ◽  
A Minor

To elucidate the major metabolic pathways of DDC analogues, the effect of inhibitors of oxidative and hydrolytic microsomal enzymes on the rate of metabolism of these compounds in chick embryo liver cell cultures has been examined. The metabolism of 3,5-diethoxycarbonyl-2,4,6-trimethylpyridine (Ox-DDC) was inhibited threefold by piperonyl butoxide and SKF-525A (β-diethylaminoethyl-diphenyl-n-propylacetate-HCl), but only onefold by bis(p-nitrophenyl)phosphate (BNPP). This indicates that this compound is metabolized predominately by an oxidative route and hydrolysis is a minor pathway. The half-life of 3,5-diethoxycarbonyl-2,6-dimethylpyridine (4-desmethyl-Ox-DDC) was increased 20-fold by BNPP, but no change was observed with piperonyl butoxide, indicating that this compound is metabolized exclusively by hydrolytic mechanisms. Since both piperonyl butoxide and BNPP produced similar changes in the half-life of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), it appears that this compound is metabolized equally via oxidative and hydrolytic mechanisms. In contrast to the intact embryo where Ox-DDC is rapidly metabolized and the effect of the agent on δ-aminolevulinic acid (δ-ALA) synthetase (δ-aminolaevulinate synthetase; EC 2.3.1.37) activity is brief and hence porphyrin accumulation does not occur, in cell culture Ox-DDC is metabolized at a rate sufficiently slow so that induction of δ-ALA synthetase does occur.

The effects of dihydropyridine calcium antagonists on heme biosynthesis in chick embryo liver cell culture

1986 ◽  
Vol 64 (4) ◽  
pp. 438-443 ◽  
Author(s):  
G. S. Marks ◽  
D. R. Goldman ◽  
S. A. McCluskey ◽  
E. P. Sutherland ◽  
M. E. Lyon
Keyword(s):  
Cell Culture ◽  
Chick Embryo ◽  
Liver Cell ◽  
Calcium Antagonists ◽  
Antagonist Activity ◽  
Liver Cell Culture ◽  
Hepatic Microsomes ◽  
Weak Activity ◽  
Embryo Liver ◽  
Cytochrome P 450

A variety of 1,4-dihydropyridine calcium antagonists were tested for porphyrinogenic activity in chick embryo liver cell culture. 3,5-Dimethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(ortho-nitrophenyl)pyridine (nifedipine) was shown to be a potent porphyrinogenic agent. This activity was shared by a number of related analogues, viz., the 4-phenyl, 4-(meta-nitrophenyl), 4-(para-nitrophenyl), 4-(ortho-methoxyphenyl), 4-(meta-trifluoromethylphenyl), and 4-(para-trifluoromethylphenyl) analogues and nitrendipine; nicardipine exhibited very weak activity. The porphyrinogenic potency of the 1,4-dihydropyridines did not parallel their calcium antagonist activity. Nifedipine did not exhibit ferrochelatase-lowering activity in chick embryo liver cell culture and uroporphyrin and heptacarboxylic acid porphyrin were the major porphyrins to accumulate. Nifedipine did not cause suicidal destruction of cytochrome P-450 in chick embryo hepatic microsomes. Because nifedipine possesses comparable porphyrinogenic activity to sodium secobarbital in chick embryo liver cell culture, caution is required if nifedipine or related drugs are administered to patients with hereditary hepatic porphyria.

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