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. 1971 Oct 31;134(5):1349–1371. doi: 10.1084/jem.134.5.1349

THE INFLUENCE OF POSTNATAL DEVELOPMENT ON DRUG-INDUCED HEPATIC PORPHYRIA AND THE SYNTHESIS OF CYTOCHROME P-450

A BIOCHEMICAL AND MORPHOLOGICAL STUDY

Chull S Song 1, Harold L Moses 1, Alan S Rosenthal 1, Nancy A Gelb 1, Attallah Kappas 1
PMCID: PMC2139010  PMID: 5112207

Abstract

The mitochondrial enzyme δ-aminolevulinate synthetase (ALAS) controls the rate-limiting step in the synthesis of porphyrins and heme. An experimental form of hepatic porphyria can be readily elicited in laboratory animals, such as the rat, by drugs and foreign chemicals which are known to enhance the de novo formation of this enzyme in the liver. The present study shows that there is a striking refractoriness to the induction of ALAS during the perinatal period in the rat. Chemicals which have potent porphyria-inducing activity in adult animals have no significant inducing effect on hepatic ALAS in neonates. The ultrastructural changes which accompany the induction of ALAS by drugs and chemicals in adult liver also fail to take place in the livers of neonates. A progressive capacity for responding to the action of chemical inducers of hepatic ALAS does, however, develop in neonatal animals so that by approximately 5–6 wk of age experimental porphyria can be elicited as effectively in them as in adults. The reasons for the refractoriness of hepatic ALAS to induction in the perinatal period are not known; but the findings of this study make it clear that ALAS belongs to that increasingly large group of liver enzymes in mammals whose appearance, increase of activity, or inducibility is developmentally determined. The occurrence of developmental changes in the indicibility of ALAS in the liver of neonates also provided an opportunity to study the relationship of this enzyme activity to the drug-mediated induction of the hepatic hemoprotein cytochrome P-450. This inducible hemoprotein serves as the terminal oxygenase in the microsomal mixed-function oxidase system in the liver. The results of this study indicate that, in contrast to the refractoriness of ALAS to induction, significant drug-induced changes of hepatic P-450 content and of hemeprecursor incorporation into this cytochrome do take place in neonates. The synthesis of P-450 thus appears to be under a regulatory control different from that of ALAS in neonates, and the relation between ALAS activity and P-450 formation is not therefore a direct one.

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Selected References

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  1. BURCH H. B., LOWRY O. H., DE GUBAREFF T., LOWRY S. R. Flavin enzymes in liver and kidney of rats from birth to weaning. J Cell Physiol. 1958 Dec;52(3):503–510. doi: 10.1002/jcp.1030520308. [DOI] [PubMed] [Google Scholar]
  2. Basu T. K., Dickerson J. W., Parke D. V. The effects of development on the activity of drug-metabolizing enzymes in the liver of the rat. Biochem J. 1970 Oct;119(5):54P–54P. doi: 10.1042/bj1190054pa. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biempica L., Kosower N. S., Nivikoff A. B. Cytochemical and ultrastructural changes in rat liver in experimental porphyria. I. Effects of a single injection of allylisopropylacetamide. Lab Invest. 1967 Aug;17(2):171–189. [PubMed] [Google Scholar]
  4. COOPER D. Y., LEVIN S., NARASIMHULU S., ROSENTHAL O. PHOTOCHEMICAL ACTION SPECTRUM OF THE TERMINAL OXIDASE OF MIXED FUNCTION OXIDASE SYSTEMS. Science. 1965 Jan 22;147(3656):400–402. doi: 10.1126/science.147.3656.400. [DOI] [PubMed] [Google Scholar]
  5. Conney A. H. Pharmacological implications of microsomal enzyme induction. Pharmacol Rev. 1967 Sep;19(3):317–366. [PubMed] [Google Scholar]
  6. Darby F. J. Changes in drug-metabolizing activities in the livers of suckling rats as a result of treatment of the lactating mothers with phenobarbitone and chlorpromazine. Biochem J. 1971 Mar;122(1):41–47. doi: 10.1042/bj1220041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davies D. S., Gigon P. L., Gillette J. R. Species and sex differences in electron transport systems in liver microsomes and their relationship to ethylmorphine demethylation. Life Sci. 1969 Jan 15;8(2):85–91. doi: 10.1016/0024-3205(69)90121-0. [DOI] [PubMed] [Google Scholar]
  8. Demus-Oole A., Swierczewski E. Glutathione peroxidase in rat liver during development. II. Changes in glutathione peroxidase during post-natal development of normal and hypotrophic rats. Biol Neonat. 1969;14(3):219–225. doi: 10.1159/000240187. [DOI] [PubMed] [Google Scholar]
  9. Doyle D., Schimke R. T. The genetic and developmental regulation of hepatic delta-aminolevulinate dehydratase in mice. J Biol Chem. 1969 Oct 25;244(20):5449–5459. [PubMed] [Google Scholar]
  10. FEIGELSON P., GREENGARD O. The activation and induction of tryptophan pyrrolase during experimental porphyria and by amino-triazole. Biochim Biophys Acta. 1961 Sep 30;52:509–516. doi: 10.1016/0006-3002(61)90409-7. [DOI] [PubMed] [Google Scholar]
  11. Feigelson M. Estrogenic regulation of hepatic histidase during postnatal development and adulthood. J Biol Chem. 1968 Oct 10;243(19):5088–5093. [PubMed] [Google Scholar]
  12. GRANICK S., URATA G. Increase in activity of alpha-aminolevulinic acid synthetase in liver mitochondria induced by feeding of 3,5-dicarbethoxy-1,4-dihydrocollidine. J Biol Chem. 1963 Feb;238:821–827. [PubMed] [Google Scholar]
  13. Ganote C. E., Moses H. L. Light and dark cells as artifacts of liver fixation. Lab Invest. 1968 Jun;18(6):740–745. [PubMed] [Google Scholar]
  14. Gordon A. S., Zanjani E. D., Levere R. D., Kappas A. Stimulation of mammalian erythropoiesis by 5beta-H steroid metabolites. Proc Natl Acad Sci U S A. 1970 Apr;65(4):919–924. doi: 10.1073/pnas.65.4.919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Granick S. The induction in vitro of the synthesis of delta-aminolevulinic acid synthetase in chemical porphyria: a response to certain drugs, sex hormones, and foreign chemicals. J Biol Chem. 1966 Mar 25;241(6):1359–1375. [PubMed] [Google Scholar]
  16. Greengard O., Dewey H. K. Initiation by glucagon of the premature development of tyrosine aminotransferase, serine dehydratase, and glucose-6-phosphatase in fetal rat liver. J Biol Chem. 1967 Jun 25;242(12):2986–2991. [PubMed] [Google Scholar]
  17. Greengard O. The hormonal regulation of enzymes in penatal and postnatal rat liver. Effects of adenosine 3',5'-(cyclic)-monophosphate. Biochem J. 1969 Oct;115(1):19–24. doi: 10.1042/bj1150019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gross S. R., Hutton J. J. Induction of hepatic delta-aminolevulinic acid synthetase activity in strains of inbred mice. J Biol Chem. 1971 Feb 10;246(3):606–614. [PubMed] [Google Scholar]
  19. Guarino A. M., Gram T. E., Gigon P. L., Greene F. E., Gillette J. R. Changes in Michaelis and spectral constants for aniline in hepatic microsomes from phenobarbital-treated rats. Mol Pharmacol. 1969 Mar;5(2):131–136. [PubMed] [Google Scholar]
  20. HERRMANN H., TOOTLE M. L. SPECIFIC AND GENERAL ASPECTS OF THE DEVELOPMENT OF ENZYMES AND METABOLIC PATHWAYS. Physiol Rev. 1964 Apr;44:289–371. doi: 10.1152/physrev.1964.44.2.289. [DOI] [PubMed] [Google Scholar]
  21. Halac E., Jr, Sicignano C. Re-evaluation of the influence of sex, age pregnancy, and phenobarbital on the activity of UDP-glucuronyl transferase in rat liver. J Lab Clin Med. 1969 Apr;73(4):677–685. [PubMed] [Google Scholar]
  22. Hayashi N., Yoda B., Kikuchi G. Mechanism of allylisopropylacetamide-induced increase of delta-aminolevulinate synthetase in liver mitochondria. IV. Accumulation of the enzyme in the soluble fraction of rat liver. Arch Biochem Biophys. 1969 Apr;131(1):83–91. doi: 10.1016/0003-9861(69)90107-6. [DOI] [PubMed] [Google Scholar]
  23. Holt P. G., Oliver I. T. Factors affecting the premature induction of tyrosine aminotransferase in foetal rat liver. Biochem J. 1968 Jun;108(2):333–338. doi: 10.1042/bj1080333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holt P. G., Oliver I. T. Plasma corticosterone concentrations in the perinatal rat. Biochem J. 1968 Jun;108(2):339–341. doi: 10.1042/bj1080339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jakubiec-Puka A., Mochnacka I. Activity of the phenylalanine hydroxylating system in liver of newborn, suckling and adult rats. Acta Biochim Pol. 1969;16(4):321–331. [PubMed] [Google Scholar]
  26. Kappas A., Granick S. Steroid induction of porphyrin synthesis in liver cell culture. II. The effects of heme, uridine diphosphate glucuronic acid, and inhibitors of nucleic acid and protein synthesis on the induction process. J Biol Chem. 1968 Jan 25;243(2):346–351. [PubMed] [Google Scholar]
  27. Kappas A., Song C. S., Sassa S., Levere R. D., Granick S. The occurrence of substances in human plasma capable of inducing the enzyme delta-aminolevulinate synthetase in liver cells. Proc Natl Acad Sci U S A. 1969 Oct;64(2):557–564. doi: 10.1073/pnas.64.2.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kurashima Y., Hayashi N., Kikuchi G. Mechanism of inhibition by hemin of increase of delta-aminolevulinate synthetase in liver mitochondria. J Biochem. 1970 Jun;67(6):863–865. doi: 10.1093/oxfordjournals.jbchem.a129320. [DOI] [PubMed] [Google Scholar]
  29. LANG C. A. RESPIRATORY ENZYMES IN THE HEART AND LIVER OF THE PRENATAL AND POSTNATAL RAT. Biochem J. 1965 May;95:365–371. doi: 10.1042/bj0950365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  31. Levere R. D., Kappas A. Biochemical and clinical aspects of the porphyrias. Adv Clin Chem. 1968;11:133–174. doi: 10.1016/s0065-2423(08)60058-x. [DOI] [PubMed] [Google Scholar]
  32. Levere R. D., Kappas A., Granick S. Stimulation of hemoglobin synthesis in chick blastoderms by certain 5beta androstane and 5beta pregnane steroids. Proc Natl Acad Sci U S A. 1967 Sep;58(3):985–990. doi: 10.1073/pnas.58.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Levin W., Kuntzman R. Biphasic decrease of radioactive hemoprotein from liver microsomal CO-binding particles. Effect of 3-methylcholanthrene. J Biol Chem. 1969 Jul 10;244(13):3671–3676. [PubMed] [Google Scholar]
  34. Linder-Horowitz M. Changes in glutaminase activities of rat liver and kidney during pre- and post-natal development. Biochem J. 1969 Aug;114(1):65–70. doi: 10.1042/bj1140065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lockwood E. A., Bailey E., Taylor C. B. Factors involved in changes in hepatic lipogenesis during development of the rat. Biochem J. 1970 Jun;118(1):155–162. doi: 10.1042/bj1180155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Marver H. S., Collins A., Tschudy D. P., Rechcigl M., Jr Delta-aminolevulinic acid synthetase. II. Induction in rat liver. J Biol Chem. 1966 Oct 10;241(19):4323–4329. [PubMed] [Google Scholar]
  37. Marver H. S., Schmid R., Schützel H. Heme and methemoglobin: naturally occurring repressors of microsomal cytochrome. Biochem Biophys Res Commun. 1968 Dec 30;33(6):969–974. doi: 10.1016/0006-291x(68)90408-7. [DOI] [PubMed] [Google Scholar]
  38. Marver H. S., Tschudy D. P., Perlroth M. G., Collins A. Delta-aminolevulinic acid synthetase. I. Studies in liver homogenates. J Biol Chem. 1966 Jun 25;241(12):2803–2809. [PubMed] [Google Scholar]
  39. Mazur A. Metabolism of the stimulated rat spleen. I. Ferrochelatase activity as an index of tissue erythropoiesis. J Clin Invest. 1968 Oct;47(10):2230–2238. doi: 10.1172/JCI105908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Miller A. L., Chu P. The development of urea cycle enzyme activity in the liver of foetal and neonatal rats. Enzymol Biol Clin (Basel) 1970;11(6):497–503. doi: 10.1159/000458392. [DOI] [PubMed] [Google Scholar]
  41. Mitani F., Alvares A. P., Sassa S., Kappas A. Preparation and properties of a solubilized form of cytochrome P-450 from chick embryo liver microsomes. Mol Pharmacol. 1971 May;7(3):280–292. [PubMed] [Google Scholar]
  42. Moses H. L., Stein J. A., Tschudy D. P. Hepatocellular changes associated with allylisopropylacetamide-induced hepatic porphyria in rats. Lab Invest. 1970 May;22(5):432–442. [PubMed] [Google Scholar]
  43. Msuya P. M., Schepartz B. Development of tyrosine-metabolizing enzymes in rat liver during the first day after birth. Biol Neonat. 1969;14(5):317–323. doi: 10.1159/000240197. [DOI] [PubMed] [Google Scholar]
  44. NEMETH A. M. Mechanisms controlling changes in tryptophan peroxidase activity in developing mammalian liver. J Biol Chem. 1959 Nov;234:2921–2924. [PubMed] [Google Scholar]
  45. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964 Jul;239:2370–2378. [PubMed] [Google Scholar]
  46. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. II. SOLUBILIZATION, PURIFICATION, AND PROPERTIES. J Biol Chem. 1964 Jul;239:2379–2385. [PubMed] [Google Scholar]
  47. Posalaki Z., Barka T. Alterations of hepatic endoplasmic reticulum in porphyric rats. J Histochem Cytochem. 1968 May;16(5):337–345. doi: 10.1177/16.5.337. [DOI] [PubMed] [Google Scholar]
  48. REMMER H., MERKER H. J. DRUG-INDUCED CHANGES IN THE LIVER ENDOPLASMIC RETICULUM: ASSOCIATION WITH DRUG-METABOLIZING ENZYMES. Science. 1963 Dec 27;142(3600):1657–1658. doi: 10.1126/science.142.3600.1657. [DOI] [PubMed] [Google Scholar]
  49. ROSE J. A., HELLMAN E. S., TSCHUDY D. P. Effect of diet on induction of experimental porphyria. Metabolism. 1961 Jul;10:514–521. [PubMed] [Google Scholar]
  50. SERENI F., KENNEY F. T., KRETCHMER N. Factors influencing the development of tyrosine-alpha-ketoglutarate transaminase activity in rat liver. J Biol Chem. 1959 Mar;234(3):609–612. [PubMed] [Google Scholar]
  51. Schwark W. S., Ecobichon D. J. Perinatal development of rat liver and kidney esterases. Biochem Pharmacol. 1969 Apr;18(4):915–921. doi: 10.1016/0006-2952(69)90062-8. [DOI] [PubMed] [Google Scholar]
  52. Stein J. A., Tschudy D. P., Corcoran P. L., Collins A. Delta-aminolevulinic acid synthetase. 3. Synergistic effect of chelated iron on induction. J Biol Chem. 1970 May 10;245(9):2213–2218. [PubMed] [Google Scholar]
  53. TADDEINI L., NORDSTROM K. L., WATSON C. J. HYPERCHOLESTEROLEMIA IN EXPERIMENTAL AND HUMAN HEPATIC PORPHYRIA. Metabolism. 1964 Aug;13:691–701. doi: 10.1016/0026-0495(64)90015-0. [DOI] [PubMed] [Google Scholar]
  54. TSCHUDY D. P., WELLAND F. H., COLLINS A., HUNTER G., Jr THE EFFECT OF CARBOHYDRATE FEEDING ON THE INDUCTION OF DELTA-AMINOLEVULINIC ACID SYNTHETASE. Metabolism. 1964 May;13:396–406. doi: 10.1016/0026-0495(64)90113-1. [DOI] [PubMed] [Google Scholar]
  55. Takesue S., Omura T. Enzymatic solubilization of microsomal NADH-cytochrome b5 reductase by lysosomes. Biochem Biophys Res Commun. 1968 Mar 27;30(6):723–729. doi: 10.1016/0006-291x(68)90573-1. [DOI] [PubMed] [Google Scholar]
  56. Tenhunen R., Marver H. S., Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem. 1969 Dec 10;244(23):6388–6394. [PubMed] [Google Scholar]
  57. Tenhunen R., Marver H. S., Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968 Oct;61(2):748–755. doi: 10.1073/pnas.61.2.748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Thompson E. B., Tomkins G. M., Curran J. F. Induction of tyrosine alpha-ketoglutarate transaminase by steroid hormones in a newly established tissue culture cell line. Proc Natl Acad Sci U S A. 1966 Jul;56(1):296–303. doi: 10.1073/pnas.56.1.296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tuboi S., Kim H. J., Kikuchi G. Occurrence of a specific and reversible inhibitor of delta-aminolevulinate synthetase in extracts of Rhodopseudomonas spheroides. Arch Biochem Biophys. 1969 Mar;130(1):92–100. doi: 10.1016/0003-9861(69)90014-9. [DOI] [PubMed] [Google Scholar]
  60. Uddin D. E., Titchener E. B. Rat liver carboxylesterase: influence of age and sex on activity and kinetics of ester hydrolysis. Comp Biochem Physiol. 1968 Sep;26(3):985–990. doi: 10.1016/0010-406x(68)90019-4. [DOI] [PubMed] [Google Scholar]
  61. Vesell E. S. Genetic and environmental factors affecting hexobarbital metabolism in mice. Ann N Y Acad Sci. 1968 Jul 31;151(2):900–912. doi: 10.1111/j.1749-6632.1968.tb48275.x. [DOI] [PubMed] [Google Scholar]
  62. Waxman A. D., Collins A., Tschudy D. P. Oscillations of hepatic delta-aminolevulinic acid synthetase produced in vivo by heme. Biochem Biophys Res Commun. 1966 Sep 8;24(5):675–683. doi: 10.1016/0006-291x(66)90377-9. [DOI] [PubMed] [Google Scholar]
  63. Wetterberg L., Yuwiler A., Geller E. Tryptophan oxygenase changes following delta-aminolevulinic acid administration in the rat. Life Sci. 1969 Oct 1;8(19):1047–1049. doi: 10.1016/0024-3205(69)90156-8. [DOI] [PubMed] [Google Scholar]
  64. Woods J. S., Dixon F. L. Perinatal differences in delta-aminolevulinic acid synthetase activity. Life Sci II. 1970 Jun 22;9(12):711–719. doi: 10.1016/0024-3205(70)90279-1. [DOI] [PubMed] [Google Scholar]
  65. Yaffe S. J., Krasner J., Catz C. S. 3. Genetic variations that modify drug response. Variations in detoxication enzymes during mammalian development. Ann N Y Acad Sci. 1968 Jul 31;151(2):887–899. doi: 10.1111/j.1749-6632.1968.tb48274.x. [DOI] [PubMed] [Google Scholar]
  66. Yeung D., Stanley R. S., Oliver I. T. Development of gluconeogenesis in neonatal rat liver. Effect of triamcinolone. Biochem J. 1967 Dec;105(3):1219–1227. doi: 10.1042/bj1051219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. de Matteis F. Disturbances of liver porphyrin metabolism caused by drugs. Pharmacol Rev. 1967 Dec;19(4):523–557. [PubMed] [Google Scholar]

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