Cytochrome P-450 heme and the regulation of δ-aminolevulinic acid synthetase in the liver

Bissell, D. Montgomery; Hammaker, Lydia

doi:10.1016/0003-9861(76)90145-4

Cited by 83 publications

(20 citation statements)

References 26 publications

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“…This is in agreement with the findings of Maines & Kappas (1976a) but conflicts with the model suggested by Bissell & Hammaker (1976). Their model considered that ALA synthase and haem oxygenase are inter-related with respect to their regulation by haem.…”

Section: Discussionsupporting

confidence: 79%

Hepatic Drug Metabolism and Haem Biosynthesis in Lead‐poisoned Rats

Goldberg

Meredith

Miller

et al. 1978

British J Pharmacology

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1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. 2 The activity of the rate-limiting enzyme of haem biosynthesis, c-aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. 3 The activity of the haem biosynthetic enzymes 6-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment. IntroductionIt has long been recognized that haem synthesis in man is severely affected by increased body lead burden. This inhibition of haem production is well known to result in decreased levels of circulating haemoglobin in lead-exposed individuals. The possibility of altered drug metabolism due to inhibition of synthesis of the microsomal haemoprotein cytochrome P-450 has been the subject of a number of studies both in man and animals.Recent reports (Alvares, Kapelner, Sassa & Kappas, 1975; Meredith, Campbell, Moore & Goldberg, 1977)

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Section: Discussionsupporting

confidence: 79%

Hepatic Drug Metabolism and Haem Biosynthesis in Lead‐poisoned Rats

Goldberg

Meredith

Miller

et al. 1978

British J Pharmacology

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“…LPS markedly reduced the activities of aminopyrine N demethylase and aniline hydroxylase in the 9,000xg supernatant of the liver homogenate and reduced cytochrome P-450 or cyto chrome b5 contents in the microsomes of the liver 24 hr after the injection. Decrease of enzyme activity induced by LPS is probably a consequence of damage to some compo nent of the electron-transport system such as cytochrome P-450 (18,19). A dose of 2.5 mg/kg, i.v., of LPS corresponds to about one twelfth the LD50 in mice.…”

Section: Discussionmentioning

confidence: 99%

Drug interaction of antitumor drugs. III. Antitumor activity of tegafur in lipopolysaccharide-treated mice.

1982

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Abstract-The effect of lipopolysaccharide (obtained from Escherichia coli, LPS) on the antitumor activity, acute toxicity and metabolism of tegafur was investigated in mice in comparison with 5-fluorouracil (5-FU). It was found that the intravenous administration of LPS (1.25 or 2.5 mg/kg) 24 hr prior to tegafur decreased the antitumor activity of tegafur against the solid form of Sarcoma 180. On the acute toxicity of tegafur or 5-FU, the lethality of the former was decreased and that of the latter was enhanced by the pretreatment with LPS 24 hr before.In LPS-treated mice, after the administration of tegafur, the level of tegafur in plasma was higher and the elevated level maintained longer than in untreated mice; and a small amount of 5-FU was released.A high level of 5-FU in plasma after the adminis tration of 5-FU was also observed in LPS-treated mice. In the liver and kidneys of LPS-treated mice, the level of 5-FU after the administration of tegafur or 5-FU was higher, and its conversion of 5-FU to fluorouridine (FUR) was lower than that of control mice. On the other hand, LPS inhibited significantly the hepatic drug-metabolizing enzymes 24 hr after. It can, therefore, be presumed that the antitumor activity of tegafur was affected with LPS as a result of inhibition of conversion from tegafur to 5-FU or from 5-FU to FUR mainly according to depression in the hepatic drug-metabolism.

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“…inhibition of ALA-S synthesis at both transcriptional and translational steps, inhibition of the enzyme transfer from cytosol into mitochondria and inhibition of its catalytic activity (12). To our knowledge, ALA-S is the only example for which the occurrence of regulation of intracellular translocation is clearly demonstrated.…”

Section: Introductionmentioning

confidence: 92%