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.

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.

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.

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.

scholarly journals Evidence that ligand formation is a mechanism underlying the maintenance of cytochrome P-450 in rat liver cell culture. Potent maintenance by metyrapone

1980 ◽  
Vol 188 (3) ◽  
pp. 937-939 ◽  
Author(s):  
A J Paine ◽  
P Villa ◽  
L J Hockin
Keyword(s):  
Cell Culture ◽  
Protein Synthesis ◽  
Rat Liver ◽  
Liver Cell ◽  
Rat Hepatocytes ◽  
Liver Cell Culture ◽  
Substituted Pyridines ◽  
Cultured Rat Hepatocytes ◽  
Highly Correlated ◽  
Cytochrome P 450

The loss of cytochrome P-450 in cultured rat hepatocytes can be prevented by substituted pyridines, especially isonicotinamide, 3-hydroxypyridine and metyrapone. The effect of these compounds is independent of protein synthesis, suggesting that they maintain pre-existing cytochrome P-450. The efficiency of pyridines at maintaining cytochrome P-450 in hepatocyte culture is highly correlated with their ability to bind to this cytochrome, suggesting that ligand formation with cytochrome P-450 prevents its accelerated turnover in liver cell culture.

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.

Long term maintenance and induction of cytochrome P-450 in rat liver cell culture

1982 ◽  
Vol 31 (6) ◽  
pp. 1175-1178 ◽  
Author(s):  
Alan J. Paine ◽  
Lesley J. Hockin ◽  
Christine M. Allen
Keyword(s):  
Cell Culture ◽  
Rat Liver ◽  
Liver Cell ◽  
Liver Cell Culture ◽  
Cytochrome P 450 ◽  
Term Maintenance

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.

Sign in / Sign up

Export Citation Format

Share Document