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Concepts in Biochemical Pharmacology pp 401–421Cite as

Metabolism of Normal Body Constituents by Drug-Metabolizing Enzymes in Liver Microsomes

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Abstract

The duration and intensity of action of many drugs are determined by the speed at which they are metabolized in the body by enzymes in liver microsomes. The activities of drug-metabolizing enzymes can be altered by dietary and nutritional factors, hormonal changes in the body and by the ingestion of foreign chemicals (Conney and Burns, 1962; Gillette, 1963; Conney, 1967). Recent studies suggest that steroid hormones, fatty acids, bilirubin and several other normal body constituents are substrates for drug-metabolizing enzymes in liver microsomes. Accordingly, changes in the activities of drug-metabolizing enzymes are reflected by changes in the metabolism of normal body constituents that are metabolized by these enzymes. This review describes some of the normal body constituents that are substrates for drug-metabolizing enzymes in liver microsomes and indicates some of the factors that influence the metabolism of these substances.

Most of the work on which this chapter is based was carried out in the laboratories of Burroughs Wellcome and Co.

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References

  • Alvares, A.P., Schilling, G., Levin, W., Kuntzman, R.: Studies on the induction of CO-binding pigments in liver microsomes by phenobarbital and 3-methylcholanthrene. Biochem. biophys. Res. Commun. 29, 521–526 (1967).

    PubMed  CAS  Google Scholar 

  • Alvares, A.P., Schilling, G., Levin, W., Kuntzman, R.: Alteration of the microsomal hemoprotein by 3-methylcholanthrene: Effects of ethionine and actinomycin D. J. Pharmacol. exp. Ther. 163, 417–424 (1968).

    PubMed  CAS  Google Scholar 

  • Arias, I.M., Gartner, L.M., Cohen, M., Ben Ezzer, J., Levi, A.J.: Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency: Clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Amer. J. Med. 47, 395–409 (1969).

    PubMed  CAS  Google Scholar 

  • Arias, I.M., Gartner, L.M., Furman, M., Wolfson, S.: Effect of several drugs and chemicals on hepatic glucuronide formation in newborn rats. Proc. Soc. exp. Biol. (N.Y.) 112, 1037–1040 (1963).

    CAS  Google Scholar 

  • Arias, I.M., Gartner, L.M., Furman, M., Wolfson, S.: Studies on the effect of several drugs on hepatic glucuronide formation in newborn rats and humans. Ann. N.Y. Acad. Sci. 111, 274–280 (1963a).

    PubMed  CAS  Google Scholar 

  • Astrup, P., Kjeldsen, K., Wanstrup, J.: Enhancing influences of carbon monoxide on the development of atheromatosis in cholesterol-fed rabbits. J. Atheroscler. Res. 7, 343–354 (1967).

    PubMed  CAS  Google Scholar 

  • Axelrod, J.: Enzymatic formation of adrenaline and other catechols from monophenols. Science 140, 499–500 (1963).

    PubMed  CAS  Google Scholar 

  • Bahr, C., von, Lisboa, B.P., Orrenius, S.: Influence of phenobarbital pretreatment on the in vitro ring A reduction of Δ4-3-oxosteroids in rat liver microsomes. Naunyn-Schmiedeberg’s Arch. exp. Path. Pharmak. 264, 420–426 (1969).

    Google Scholar 

  • Bernhard, K., von Bulow-Koster, J., Wagner, H.: Die Enzymatische Dehydrierung der Stearinsäure zu Ölsäure. Helv. chim. Acta 42, 152–155 (1959).

    CAS  Google Scholar 

  • Bernstein, G., Artz, S.A., Hasen, J., Oppenheimer, J.H.: Hepatic accumulation of 125I-thyroxine in the rat: Augmentation by phenobarbital and chlordane. Endocrinology 82, 406–409 (1968).

    PubMed  CAS  Google Scholar 

  • Berquist, P.L., Matthews, R.E.F.: Distribution of methylated purines in cell fractions from mouse liver and tumor. Biochim. biophys. Acta (Amst.) 34, 567–569 (1959).

    Google Scholar 

  • Bitman, J., Cecil, H.C., Harris, S.J., Fries, G.F.: Estrogenic activity of o,p’-DDT in the mammalian uterus and avian oviduct. Science 162, 371–372 (1968).

    PubMed  CAS  Google Scholar 

  • Bledsoe, T., Island, D.P., Ney, R.L., Liddle, G.W.: An effect of o,p’-DDD on the extraadrenal metabolism of Cortisol in man. J. clin. Endocr. 24, 1303–1311 (1964).

    PubMed  CAS  Google Scholar 

  • Bloch, K.: The biological synthesis of cholesterol. Science 150, 19–28 (1965).

    PubMed  CAS  Google Scholar 

  • Boggs, T.R., Hardy, J.B., Frazier, T.M.: Correlation of neonatal serum total bilirubin concentrations and developmental status at age eight months. A preliminary report from the collaborative project. J. Pediat. 71, 553–560 (1967).

    PubMed  Google Scholar 

  • Boyd, G.S., Scholan, N.A., Mitton, J.R.: Factors influencing cholesterol 7α-hydroxylase activity in the rat liver. Plenum Press, New York. Ed. by W.L. Holmes, L.A. Carlson and R. Paoletti. Advanc. exp. Med. Biol. 4, 443–456 (1969).

    Google Scholar 

  • Burstein, S., Bhavnani, B.R.: Effect of phenobarbital administration on the in vitro hydroxylation of Cortisol and on over-all substrate and product metabolism in the guinea pig and rat. Endocrinology 80, 351–356 (1967).

    PubMed  CAS  Google Scholar 

  • Burstein, S., Klaiber, E.L.: Phenobarbital-induced increases in 6β-hydroxycortisol excretion: Clue to its significance in human urine. J. clin. Endocr. 25, 293–296 (1965).

    PubMed  CAS  Google Scholar 

  • Catz, C., Yaffe, S.J.: Pharmacological modification of bilirubin conjugation in the newborn. Amer. J. Dis. Child. 104, 516–517 (1962).

    Google Scholar 

  • Catz, C., Yaffe, S.J.: Barbiturate enhancement of bilirubin conjugation and excretion in young and adult animals. Pediat. Res. 2, 361–370 (1968).

    PubMed  CAS  Google Scholar 

  • Coburn, R.F.: Effect of phenobarbital on endogenous carbon monoxide production in normal man. J. clin. Invest. 46, 1046 (1967).

    Google Scholar 

  • Colas, A.: The 16α-hydroxylation of dehydroepiandrosterone (3β-hydroxyandrost-5-en-17-one) by rat liver slices. Biochem. J. 82, 390–394 (1962).

    PubMed  CAS  Google Scholar 

  • Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev. 19, 317–366 (1967).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Burns, J.J.: Factors influencing drug metabolism. Advanc. Pharmacol. 1, 31–58 (1962).

    CAS  Google Scholar 

  • Conney, A.H., Davison, C., Gastel, R., Burns, J.J.: Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J. Pharmacol. exp. Ther. 130, 1–8 (1960).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Gillette, J.R., Inscoe, J.K., Trams, E.C., Posner, H.S.: 3,4-Benzpyrene-induced synthesis of liver microsomal enzymes which metabolize foreign compounds. Science 130, 1478–1479 (1959).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Jacobson, M., Levin, W., Schneidman, K., Kuntzman, R.: Decreased central depressant effect of progesterone and other steroids in rats pretreated with drugs and insecticides. J. Pharmacol. exp. Ther. 154, 310–318 (1966).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Jacobson, M., Schneidman, K., Kuntzman, R.: Induction of liver microsomal Cortisol 6β-hydroxylase by diphenylhydantoin or phenobarbital. An explanation for the increased excretion of 6-hydroxycortisol in humans treated with these drugs. Life Sci. 4, 1091–1098 (1965).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Klutch, A.: Increased activity of androgen hydroxylases in liver microsomes of rats pretreated with phenobarbital and other drugs. J. biol. Chem. 238, 1611–1617 (1963).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Levin, W., Ikeda, M., Kuntzman, R., Cooper, D.Y., Rosenthal, O.: Inhibitory effect of carbon monoxide on the hydroxylation of testosterone by rat liver microsomes. J. biol. Chem. 243, 3912–3915 (1968).

    PubMed  CAS  Google Scholar 

  • Conney, A.H., Levin, W., Jacobson, M., Kuntzman, R., Cooper, D.Y., Rosenthal, O.: Specificity in the regulation of the 6β-, 7α-and 16α-hydroxylation of testosterone by rat liver microsomes, pp. 279–295. “Microsomes and Drug Oxidations” Academic Press (1969)

    Google Scholar 

  • Conney, A.H., Schneidman, K.: Enhanced androgen hydroxylase activity in liver microsomes of rats and dogs treated with phenylbutazone. J. Pharmacol. exp. Ther. 146, 225–235 (1964).

    PubMed  CAS  Google Scholar 

  • Cooper, D.Y., Levine, S., Narasimhulu, S., Rosenthal, O., Estabrook, R.W.: Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems. Science 147, 400–402 (1965).

    PubMed  CAS  Google Scholar 

  • Cram, R.L., Juchau, M.R., Fouts, J.R.: Differences in hepatic drug metabolism in various rabbit strains before and after pretreatment with phenobarbital. Proc. Soc. exp. Biol. (N.Y.) 118, 872–875 (1965).

    CAS  Google Scholar 

  • Creaven, P.J., Parke, D.V.: The stimulation of hydroxylation by carcinogenic and noncarcinogenic compounds. Biochem. Pharmacol. 15, 7–16 (1966).

    PubMed  CAS  Google Scholar 

  • Crigler, J.F., jr., Gold, N.I.: Sodium phenobarbital-induced decrease in serum bilirubin in an infant with congenital nonhemolytic jaundice and kernicterus. J. clin. Invest. 45, 998–999 (1966).

    Google Scholar 

  • Crigler, J.F., jr., Gold, N.I.: Effect of sodium phenobarbital on bilirubin metabolism in an infant with congenital, nonhemolytic unconjugated hyperbilirubinemia and kernicterus. J. clin. Invest. 48, 42–55 (1969).

    PubMed  CAS  Google Scholar 

  • Danielsson, H., Einarsson, K.: On the conversion of cholesterol to 7α-, 12α-dihydroxycholest-4-en-3-one. Bile acids and steroids 168. J. biol. Chem. 241, 1449–1454 (1966)

    PubMed  CAS  Google Scholar 

  • Danielsson, H., Tchen, T.T.: Steroid metabolism. In: Metabolic Pathways, pp. 117–168. Ed. by D.M. Greenberg. New York: Academic Press 1968.

    Google Scholar 

  • Das, M.L., Orrenius, S., Ernster, L.: On the fatty acid and hydrocarbon hydroxylation in rat liver microsomes. Eur. J. Biochem. 4, 519–523 (1968).

    PubMed  CAS  Google Scholar 

  • De Castro, R.T., Price, J.M., Brown, R.R.: Reduced triphosphopyridine nucleotide requirement for the enzymatic formation of 3-hydroxykynurenine from L-kynurenine. J. Amer. chem. Soc. 78, 2904–2905 (1956).

    Google Scholar 

  • De Leon, A., Garter, L.M., Arias, I.M.: The effect of phenobarbital on hyperbilirubinemia in glucuronyl transferase deficient rats. J. Lab. clin. Med. 70, 273–278 (1967).

    Google Scholar 

  • Dunn, D.B.: Additional components in ribonucleic acid of rat liver fractions. Biochim.biophys. Acta (Amst.) 34, 286–288 (1959).

    CAS  Google Scholar 

  • Dutton, D.J.: (ed): Glucuronic acid. New York: Academic Press 1966.

    Google Scholar 

  • Einarsson, K., Johansson, G.: Effect of phenobarbital on the conversion of cholesterol to taurocholic acid. Bile acids and steroids 204. Eur. J. Biochem. 6, 293–298 (1968).

    PubMed  CAS  Google Scholar 

  • Einarsson, K., Johansson, G.: Effect of carbon monoxide and phenobarbital on hydroxylation of bile acids by rat liver microsomes. FEBS Letters 4, 177–180 (1969).

    PubMed  CAS  Google Scholar 

  • Ertel, I.J., Newton, W.A., jr.: Therapy in congenital hyperbilirubinemia: Phenobarbital and diethylnicotinamide. Pediatrics 44, 43–48 (1969).

    PubMed  CAS  Google Scholar 

  • Fahim, M.S., King, R.M., Hall, D.G.: Induced alterations in the biologic activity of estrogen. Amer. J. Obstet. Gynec. 100, 171–175 (1968a).

    CAS  Google Scholar 

  • Fahim, M.S., King, T.M.: Effect of phenobarbital on lactation and the nursing neonate. Amer. J. Obstet. Gynec. 101, 1103–1108 (1968).

    PubMed  CAS  Google Scholar 

  • Gaylor, J.L., Mason, H.S.: Investigation of the component fractions of oxidative sterol demethylation. J. biol. Chem. 243, 4966–4972 (1968).

    PubMed  CAS  Google Scholar 

  • Gillette, J.R.: Metabolism of drugs and other compounds by enzymatic mechanisms. Progr. Drug Res. 6, 11–73 (1963).

    CAS  Google Scholar 

  • Gillette, J.R.: Biochemistry of drug oxidation and reduction by enzymes in hepatic endoplasmic reticulum. Advanc. Pharmacol. 4, 219–261 (1966).

    CAS  Google Scholar 

  • Goldstein, J.A., Taurog, A.: Enhanced biliary excretion of thyroxine glucuronide in rats pretreated with benzpyrene. Biochem. Pharmacol. 17, 1049–1065 (1968).

    PubMed  CAS  Google Scholar 

  • Hagino, N., Ramaley, J.A., Gorski, R.A.: Inhibition of estrogen-induced precocious ovulation by pentobarbital in the rat. Endocrinology 79, 451–454 (1966).

    PubMed  CAS  Google Scholar 

  • Harbison, R.D., Spratt, J.L.: Novobiocin-induced hyperbilirubinemia and its reduction by phenobarbital pretreatment. Toxicol. appl. Pharmacol. 11, 257–263 (1967).

    CAS  Google Scholar 

  • Hart, L.G., Adamson, R.H., Dixon, R.L., Fouts, J.R.: Stimulation of hepatic microsomal drug metabolism in the newborn and fetal rabbit. J. Pharmacol. exp. Ther. 137, 103–106 (1962).

    PubMed  CAS  Google Scholar 

  • Heinrichs, W.L., Feder, H.H., Colas, A.: The steroid 16a-hydroxylase system in mammalian liver. Steroids 7, 91–98 (1966).

    PubMed  CAS  Google Scholar 

  • Hernandez, P.H., Mazel, P., Gillette, J.R.: Studies on the mechanism of action of mammalian hepatic azo reductase-II. The effects of phenobarbital and 3-methylcholanthrene on carbon monoxide sensitive and insensitive azo reductase activities. Biochem. Pharmacol. 16, 1877–1888 (1967).

    PubMed  CAS  Google Scholar 

  • Hildebrandt, A., Remmer, H., Estabrook, R.W.: Cytochrome P-450 of liver microsomes — one pigment or many. Biochem. biophys. Res. Commun. 30, 607–612 (1968).

    PubMed  CAS  Google Scholar 

  • Holloway, P.W., Peluffo, R., Wakil, S.J.: On the biosynthesis of dienoic fatty acid by animal tissues. Biochem. biophys. Res. Commun. 12, 300–304 (1963).

    PubMed  CAS  Google Scholar 

  • Ichihara, K., Kusunose, E., Kusunose, M.: Some properties and distribution of the ω-hydroxylation system of medium-chain fatty acids. Biochim. biophys. Acta (Amst.) 176, 704–712 (1969).

    CAS  Google Scholar 

  • Inscoe, J.K., Axelrod, J.: Some factors affecting glucuronide formation in vitro. J. Pharmacol. exp. Ther. 129, 128–131 (1960).

    PubMed  CAS  Google Scholar 

  • Inscoe, J.K., Daly, J., Axelrod, J.: Factors affecting the enzymatic formation of o-methylated dihydroxy derivatives. Biochem. Pharmacol. 14, 1257–1263 (1965).

    PubMed  CAS  Google Scholar 

  • Jaccarini, A., Jepson, J.B.: Enzymic 6-hydroxylation of indolealkylamines and related compounds. Biochim. biophys. Acta (Amst.) 156, 347–363 (1968).

    CAS  Google Scholar 

  • Jacobson, M., Kuntzman, R.: Studies on testosterone hydroxylation and pentobarbital oxidation by rat liver microsomes: Selective effect of age, sex, castration and testosterone propionate treatment. Steroids 13, 327–341 (1969).

    PubMed  CAS  Google Scholar 

  • Jepson, J.B., Zaltzman, P., Udenfriend, S.: Microsomal hydroxylation of tryptamine indoleacetic acid and related compounds to 6-hydroxy derivatives. Biochim. biophys. Acta (Amst.) 62, 91–102 (1962).

    CAS  Google Scholar 

  • Jones, A.L., Armstrong, D.T.: Increased cholesterol biosynthesis following phenobarbital induced hypertrophy of agranular endoplasmic reticulum in liver. Proc. Soc. exp. Biol. (N.Y.) 119, 1136–1139 (1965).

    CAS  Google Scholar 

  • Jones, P.D., Holloway, P.W., Peluffo, R.O., Wakil, S.J.: A requirement for lipids by the microsomal stearyl coenzyme A desaturase. J. biol. Chem. 244, 744–754 (1969).

    PubMed  CAS  Google Scholar 

  • Kashiwamata, S., Nakashima, K., Kotake, Y.: Anthranilic acid hydroxylation by rabbit liver microsomes. Biochim. biophys. Acta (Amst.) 113, 244–254 (1966).

    CAS  Google Scholar 

  • Kato, R., Gillette, J.R.: Sex differences in the effects of abnormal physiological states on the metabolism of drugs by rat liver microsomes. J. Pharmacol. exp. Ther. 150, 285–291 (1965).

    PubMed  CAS  Google Scholar 

  • Kato, R., Onoda, K., Omori, Y.: Effect of phenobarbital on biosynthesis and elimination of cholesterol in rats. Jap. J. Pharmacol. 18, 514–515 (1968).

    PubMed  CAS  Google Scholar 

  • Kato, R., Takahashi, A., Omori, Y.: Hydroxylation of steroid hormone by the liver microsomes of rats under pathological states. Life Sci. 7, 915–920 (1968a).

    PubMed  CAS  Google Scholar 

  • Kido, R., Noguchi, R., Kaseda, H., Kawamoto, M., Matsumara, Y.: Formation of 5-hydroxy-L-kynurenine from L-kynurenine by hen liver microsomes. Arch. Biochem. 125, 1030–1031 (1968).

    PubMed  CAS  Google Scholar 

  • Kjeldsen, K.: Carboxyhaemoglobin and serum cholesterol levels in smokers correlated to the incidence of occlusive arterial disease. Abstracts of the Second International Symposium on Atherosclerosis (Chicago), 1969, p 30.

    Google Scholar 

  • Kopin, I.J., Pare, C.M.B., Axelrod J., Weissbach, H.: The fate of melatonin in animals. J. biol. Chem. 236, 3072–3075 (1961).

    PubMed  CAS  Google Scholar 

  • Kreek, M.J., Sleisenger, M.H.: Reduction of serum-unconjugated bilirubin with phenobarbitone in adult congenital nonhemolytic unconjugated hyperbilirubinemia. Lancet 1968 II, 73–77.

    CAS  Google Scholar 

  • Kuntzman, R., Jacobson, M., Conney, A.H.: Effect of phenylbutazone on Cortisol metabolism in man. Pharmacologist 8, 195 (1966).

    Google Scholar 

  • Kuntzman, R., Jacobson, M., Levin, W., Conney, A.H.: Stimulatory effect of N-phenylbarbital (phetharbital) on Cortisol hydroxylation in man. Biochem. Pharmacol. 17, 565–571 (1968).

    PubMed  CAS  Google Scholar 

  • Kuntzman, R., Jacobson, M., Schneidman, K., Conney, A.H.: Similarities between oxidative drug-metabolizing enzymes and steroid hydroxylases in liver microsomes. J. Pharmacol. exp. Ther. 146, 280–285 (1964).

    PubMed  CAS  Google Scholar 

  • Kuntzman, R., Lawrence, D., Conney, A.H.: Michaelis constants for the hydroxylation of steroid hormones and drugs by rat liver microsomes. Mol. Pharmacol. 1, 163–167 (1965).

    PubMed  CAS  Google Scholar 

  • Kuntzman, R., Levin, W., Jacobson, M., Conney, A.H.: Studies on microsomal hydroxylation and the demonstration of a new CO-binding pigment in liver microsomes. Life Sci. 7, 215–224 (1968a).

    CAS  Google Scholar 

  • Kuntzman, R., Sansur, M., Conney, A.H.: Effect of drugs and insecticides on the anesthetic action of steroids. Endocrinology 77, 952–954 (1965a).

    PubMed  CAS  Google Scholar 

  • Kuntzman, R., Southren, A.L.: The effects of CNS active drugs on the metabolism of steroids in man. Adv. Biochem. Psychopharm. 1, 206–217 (1969).

    Google Scholar 

  • Kuntzman, R., Welch, R., Conney, A.H.: Factors influencing steroid hydroxylases in liver microsomes. In: Adv. Enzyme Reg. 4, 149–160 (1966a). Ed. by Weber, G. New York: MacMillan.

    Google Scholar 

  • Kupfer, D., Peets, L.: The effect of o,p’-DDD on Cortisol and hexobarbital metabolism. Biochem. Pharmacol. 15, 573–581 (1966).

    PubMed  CAS  Google Scholar 

  • Lemberger, L., Kuntzman, R., Conney, A.H., Burns, J.J.: Metabolism of tyramine to dopamine by liver microsomes. J. Pharmacol. exp. Ther. 150, 292–297 (1965).

    PubMed  CAS  Google Scholar 

  • Levin, W., Alvares, A.P., Jacobson, M., Kuntzman, R.: Effect of storage of frozen liver microsomal preparations on the hydroxylation of testosterone and pentobarbital and the N-demethylation of ethylmorphine. Biochem. Pharmacol. 18, 883–889 (1969a).

    PubMed  CAS  Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Effect of chronic phenobarbital treatment On the liver microsomal metabolism and uterotropic action of 17β-estradiol. Endocrinology 80, 135–140 (1967).

    PubMed  CAS  Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Effect of phenobarbital and other drugs on the metabolism and uterotropic action of estradiol-17β and estrone. J. Pharmacol. exp. Ther. 159, 362–371 (1968).

    PubMed  CAS  Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Decreased uterotropic potency of oral contraceptives in rats pretreated with phenobarbital. Endocrinology 83, 149–156 (1968a).

    PubMed  CAS  Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Estrogenic action of DDT and its analogs. Fed. Proc. 27, 649 (1968b).

    Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Inhibitory effect of phenobarbital or chlordane pretreatment on the androgen-induced increase in seminal vesicle weight in the rat. Steroids 13, 155–161 (1969).

    PubMed  CAS  Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Effect of carbon tetrachloride and other inhibitors of drug metabolism on the metabolism and action of estradiol-17β and estrone in the rat. J. Pharmacol. exp. Ther. 173, 247–255 (1970).

    PubMed  CAS  Google Scholar 

  • Levin, W., Welch, R.M., Conney, A.H.: Unpublished observations (1970a).

    Google Scholar 

  • Leybold, K., Staudinger, Hj.: Geschlechtsunterschiede im Steroidstoffwechsel von Rattenlebermikrosomen. Biochem. Z. 331, 389–398 (1959).

    CAS  Google Scholar 

  • Lu, A.Y.H., Coon, M.J.: Role of hemoprotein P-450 in fatty acid ω-hydroxylation in a soluble enzyme system from liver microsomes. J. biol. Chem. 243, 1331–1332 (1968).

    PubMed  CAS  Google Scholar 

  • Lu, A.Y.H., Junk, K.W., Coon, M.J.: Resolution of the cytochrome P-450-containing ω-hydroxylation system of liver microsomes into three components. J. biol. Chem. 244, 3714–3721 (1969).

    PubMed  CAS  Google Scholar 

  • Lu, A.Y.H., Strobel, H.W., Coon, M.J.: Hydroxylation of benzamphetamine and other drugs by a solubilized form of cytochrome P-450 from liver microsomes: Lipid requirement for drug demethylation. Biochem. biophys. Res. Commun. 36, 545–551 (1969a).

    PubMed  CAS  Google Scholar 

  • Marsh, J.B., James, A.T.: The conversion of stearic to oleic acid by liver and yeast preparations. Biochim. biophys. Acta (Amst.) 60, 320–328 (1962).

    CAS  Google Scholar 

  • Maurer, H.M., Wolff, J.A., Finster, M., Poppers, P., Pantuck, E., Kuntzman, R., Conney, A.H.: Reduction in concentration of total serum bilirubin in offspring of women treated with phenobarbitone during pregnancy. Lancet II, 122–124 (1968).

    Google Scholar 

  • Mazel, P., Henderson, J.F., Axelrod, J.: S-Demethylation by microsomal enzymes. J. Pharmacol. exp. Ther. 143, 1–6 (1964).

    PubMed  CAS  Google Scholar 

  • Mazel, P., Kerza-Kwiatecki, A., Simanis, J.: Studies on the demethylation of puromycin and related compounds by liver microsomal enzymes. Biochim. biophys. Acta (Amst.) 114, 72–82 (1966).

    CAS  Google Scholar 

  • Middleton, W.R.J., Isselbacher, K.J.: The stimulation of intestinal cholesterogenesis in the rat by phenobarbital. Proc. Soc. exp. Biol. (N.Y.) 131, 1435–1437 (1969).

    CAS  Google Scholar 

  • Miller, W.L., Kalafer, M.E., Gaylor, J.L., Delwich, C.V.: Investigation of the component reactions of oxidative sterol demethylation. Study of the aerobic and anaerobic processes. Biochemistry 6, 2673–2678 (1967).

    PubMed  CAS  Google Scholar 

  • Mitoma, C., Yasuda, D., Tagg, J.S., Neubauer, S.E., Calderoni, F.J., Tanabe, M.: Effects of various chemical agents on drug metabolism and cholesterol biosynthesis. Biochem. Pharmacol. 17, 1377–1383 (1968).

    PubMed  CAS  Google Scholar 

  • Mosbach, E.H.: Drugs affecting lipid metabolism. In: Effect of drugs on bile acid metabolism, vol. 4, pp. 421–442. Ed. by W.L. Holmes, L.A. Carlson and R. Paoletti 1969. New York: Plenum Press.

    Google Scholar 

  • Mueller, G.C., Rumney, G.: Formation of 6β-hydroxy and 6-keto derivatives of estradiol-16-C14 by mouse liver microsomes. J. Amer. chem. Soc. 79, 1004–1005 (1957).

    CAS  Google Scholar 

  • Newman, W.C., Moon, R.C.: Altered thyroxine metabolism resulting from the chemical carcinogen 3-methylcholanthrene. Endocrinology 80, 896–900 (1967).

    PubMed  CAS  Google Scholar 

  • Omura, T., Sato, R., Cooper, D.Y., Rosenthal, O., Estabrook, R.W.: Function of cytochrome P-450 of microsomes. Fed. Proc. 24, 1181–1189 (1965).

    PubMed  CAS  Google Scholar 

  • Oppenheimer, J.H., Bernstein, G., Surks, M.I.: Increased thyroxine turnover and thyroidal function after stimulation of hepatocellular binding of thyroxine by phenobarbital. J. clin. Invest. 47, 1399–1406 (1968).

    PubMed  CAS  Google Scholar 

  • Orrenius, S., Thor, H.: Fatty acid interaction with the hydroxylating enzyme system of rat liver microsomes. Eur. J. Biochem. 9, 415–418 (1969).

    PubMed  CAS  Google Scholar 

  • Oshino, N., Imai, Y., Sato, R.: Electron-transfer mechanism associated with fatty acid desaturation catalyzed by liver microsomes. Biochim. biophys. Acta (Amst.) 128, 13–28 (1966).

    CAS  Google Scholar 

  • Peakall, D.B.: Pesticide-induced enzyme breakdown of steroids in birds. Nature (Lond.) 216, 505–506 (1967).

    CAS  Google Scholar 

  • Poland, A., Kuntzman, R., Jacobson, M., Smith, D., Conney, A.H.: Clin. Pharmacol. Ther. (in press) (1970).

    Google Scholar 

  • Preiss, B., Bloch, K.: Omega-oxidation of long chain fatty acids in rat liver. J. biol. Chem. 239, 85–88 (1964).

    PubMed  CAS  Google Scholar 

  • Ramboer, C., Thompson, R.P.H., Williams, R.: Controlled trials of phenobarbitone therapy in neonatal jaundice. Lancet I, 966–968 (1969).

    Google Scholar 

  • Remmer, H., Merker, H.J.: Drug-induced changes in the liver endoplasmic reticulum: Association with drug-metabolizing enzymes. Science 142, 1657–1658 (1963).

    PubMed  CAS  Google Scholar 

  • Remmer, H., Merker, H.J.: Effect of drugs on the formation of smooth endoplasmic reticulum and drug-metabolizing enzymes. Ann. N.Y. Acad. Sci. 123, 79–97 (1965).

    PubMed  CAS  Google Scholar 

  • Robbins, K.C.: In vitro enzymic omega oxidation of medium-chain fatty acids in mammalian tissue. Biochem. Biophys. 123, 531–538 (1968).

    CAS  Google Scholar 

  • Roberts, R.J., Plaa, G.L.: Effect of phenobarbital on the excretion of an exogenous bilirubin load. Biochem. Pharmacol. 16, 827–835 (1967).

    PubMed  CAS  Google Scholar 

  • Robinson, S.H.: Increased bilirubin conjugation in heterozygous Gunn rats treated with phenobarbital. Nature (Lond.) 222, 990–991 (1969).

    CAS  Google Scholar 

  • Saito, Y., Hayaishi, O., Rothberg, S.: Studies on oxygenases; Enzymatic formation of 3-hydroxy-L-kynurenine from L-kynurenine. J. biol. Chem. 229, 921–934 (1957).

    PubMed  CAS  Google Scholar 

  • Salvador, R.A., Atkins, C., Haber, S., Kozma, C., Conney, A.H.: Changes in the serum concentration of cholesterol, triglycerides and phospholipids in the mouse and rat administered either chlorcyclizine or phenobarbital. Biochem. Pharmacol. 19, 1463–1469 (1970).

    PubMed  CAS  Google Scholar 

  • Salvador, R.A., Atkins, C., Haber, S., Kozma, C., Conney, A.H.: Effect of phenobarbital and chlorcyclizine on the development of atheromatosis in the cholesterol-fed rabbit. Biochem. Pharmacol. 19, 1975–1981 (1970).

    PubMed  CAS  Google Scholar 

  • Salvador, R.A., Conney, A.H., Kozma, C.: Inhibitory effect of phenobarbital on cholesterol-induced atherosclerosis in the rabbit. Pharmacologist. 9, 254 (1967).

    Google Scholar 

  • Schmid, R., Marver, H.S., Hammaker, L.: Enhanced formation of rapidly labeled bilirubin by phenobarbital: Hepatic microsomal cytochromes as a possible source. Biochem. biophys. Res. Commun. 24, 319–328 (1966).

    PubMed  CAS  Google Scholar 

  • Schwartz, H.L., Kosyreff, V., Surks, M.I., Oppenheimer, J.H.: Increased deiodination of L-thyroxine and L-triiodothyronine by liver microsomes from rats treated with phenobarbital. Nature (Lond.) 221, 1262–1263 (1969).

    CAS  Google Scholar 

  • Sereni, F., Perletti, L., Marini, A.: Influence of diethylnicotinamide on the concentration of serum bilirubin of newborn infants. Pediatrics 40, 446–449 (1967).

    PubMed  CAS  Google Scholar 

  • Shefer, S., Hauser, S., Mosbach, E.: 7α-Hydroxylation of cholestanol by rat liver microsomes. J. Lipid Res. 9, 328–333 (1968).

    PubMed  CAS  Google Scholar 

  • Singhal, R.L., Valadares, J.R.E., Ling, G.M.: Influence of chronic phenobarbitone treatment on uterine phosphofructokinase induction. J. Pharm. Pharmacol. 19, 545–547 (1967).

    PubMed  CAS  Google Scholar 

  • Sladek, N.E., Mannering, G.J.: Evidence for a new P-450 hemoprotein in hepatic microsomes from methylcholanthrene-treated rats. Biochem. biophys. Res. Commun. 24, 668–674 (1966).

    CAS  Google Scholar 

  • Southren, A.L., Gordon, G.G., Tochtmoto, S., Krikun, E., Krieger, D.: Effect of N-phenylbarbital (phetharbital) on the metabolism of testosterone and Cortisol in man. J. clin. Endocr. 29, 251–256 (1969).

    PubMed  CAS  Google Scholar 

  • Southren, A.L., Tochimoto, S., Strom, L., Ratuschni, A., Ross, H., Gordon, G.: Remission in Cushing’s syndrome with o,p’-DDD. J. clin. Endocr. 26, 268–278 (1966).

    PubMed  CAS  Google Scholar 

  • Stanbury, J.B., Morris, M.L., Corrigan, H.J., Lassiter, W.E.: Thyroxine deiodination by a microsomal preparation requiring Fe++, oxygen and cysteine or glutathione. Endocrinology 67, 353–362 (1960).

    CAS  Google Scholar 

  • Stoffel, W.: Biosynthesis of polyenoic fatty acids. Biochem. biophys. Res. Commun. 6, 270–273 (1961).

    PubMed  CAS  Google Scholar 

  • Suzuki, M., Mitropoulos, K.A., Myant, N.B.: The electron transport mechanism associated with 12α-hydroxylation of C27 steroids. Biochem. biophys. Res. Commun. 30, 516–521 (1968).

    PubMed  CAS  Google Scholar 

  • Tenhunen, R., Marver, H.S., Schmid, R.: The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc. nat. Acad. Sci. (Wash.) 61, 748–755 (1968).

    CAS  Google Scholar 

  • Tenhunen, R., Marver, H.S., Schmid, R.: Microsomal heme oxygenase: Characterization of the enzyme. J. biol. Chem. 244, 6388–6394 (1969).

    PubMed  CAS  Google Scholar 

  • Tenhunen, R., Ross, M.E., Marver, H.S., Schmid, R.: NADPH-Dependent biliverdin reductase: Partial purification and characterization. Biochemistry 9, 298–303 (1970).

    PubMed  CAS  Google Scholar 

  • Tephly, T.R., Mannering, G.J.: Inhibition of drug metabolism. V. Inhibition of drug metabolism by steroids. Mol. Pharmacol. 4, 10–14 (1968).

    PubMed  CAS  Google Scholar 

  • Thompson, R.P.H., Eddleston, A.L.W.P., Williams, R.: Low plasma-bilirubin in epileptics on phenobarbitone. Lancet I, 21–22 (1969).

    Google Scholar 

  • Thompson, R.P.H., Pilcher, C.W.T., Robinson, J., Stathers, G.M., McLean, A.E.M., Williams, R.: Treatment of unconjugated jaundice with dicophane. Lancet II, 4–6 (1969a).

    Google Scholar 

  • Thompson, R.P.H., Williams, R.: Treatment of chronic intrahepatic cholestasis with phenobarbitone. Lancet II, 646–648 (1967).

    Google Scholar 

  • Trolle, D.: Phenobarbitone and neonatal icterus. Lancet I, 251–252 (1968).

    Google Scholar 

  • Trolle, D.: Decrease of total serum bilirubin concentration in newborn infants, after phenobarbitone treatment. Lancet II, 705–708 (1968a).

    CAS  Google Scholar 

  • Voigt, W., Hsia, S.L., Cooper, D.Y., Rosenthal, O.: Photoreactivation spectrum of the CO-inhibited taurochenodeoxycholate 6β-hydroxylase system. FEBS Letters 2, 124–126 (1968a).

    PubMed  CAS  Google Scholar 

  • Voigt, W., Thomas, P.J., Hsia, S.L.: Enzymic studies of bile acid metabolism. I. 6β-Hydroxylation of chenodeoxycholic and taurochenodeoxycholic acids by microsomal preparations of rat liver. J. biol. Chem. 243, 3493–3499 (1968).

    PubMed  CAS  Google Scholar 

  • Wada, F., Hirata, K., Sakamoto, Y.: Relation of cholesterol synthesis and NADPH oxidation by microsomal electron transport system involving P-450. Biochim. biophys. Acta (Amst.) 143, 273–275 (1967).

    CAS  Google Scholar 

  • Wada, F., Hirata, K., Sakamoto, Y.: Possible participation of cytochrome P-450 in cholesterol synthesis. J. Biochem. (Tokyo) 65, 171–175 (1969).

    CAS  Google Scholar 

  • Wada, F., Kazuya, H., Kasuyasu, N., Sakamoto, Y.: Participation of P-450 in 7α-hydroxylation of cholesterol. J. Biochem. (Tokyo) 64, 415–417 (1968).

    CAS  Google Scholar 

  • Wada, F., Shibata, H., Goto, M., Sakamoto, Y.: Participation of the microsomal electron transport system involving cytochrome P-450 in ω-oxidation of fatty acids. Biochim. biophys. Acta (Amst.) 162, 518–524 (1968a).

    CAS  Google Scholar 

  • Wada, O., Toyokawa, K., Urata, G., Yano, Y., Nakao, K.: Cholesterol biosynthesis in the liver of experimentally induced porphyric mice. Biochem. Pharmacol. 18, 1533–1535 (1969a).

    PubMed  CAS  Google Scholar 

  • Wakabayashi, K., Shimazono, N.: Studies on omega-oxidation of fatty acids in vitro. I. Overall reaction and intermediate. Biochim. biophys. Acta (Amst.) 70, 132–142 (1963).

    CAS  Google Scholar 

  • Welch, R.M., Levin, W., Conney, A.H.: Insecticide inhibition and stimulation of steroid hydroxylases in rat liver. J. Pharmacol. exp. Ther. 155, 167–173 (1967).

    PubMed  CAS  Google Scholar 

  • Welch, R.M., Levin, W., Conney, A.H.: Stimulatory effect of phenobarbital on the metabolism in vivo of estradiol-17β and estrone in the rat. J. Pharmacol. exp. Ther. 160, 171–178 (1968).

    PubMed  CAS  Google Scholar 

  • Welch, R.M., Levin, W., Conney, A.H.: Estrogenic action of DDT and its analogs. Toxicol. appl. Pharmacol. 14, 358–367 (1969).

    PubMed  CAS  Google Scholar 

  • Welch, R.M., Levin, W., Conney, A.H.: Unpublished observations (1970).

    Google Scholar 

  • Werk, E.E., jr., Macgee, J., Sholiton, L.J.: Effect of diphenylhydantoin on Cortisol metabolism in man. J. clin. Invest. 43, 1824–1835 (1964).

    PubMed  CAS  Google Scholar 

  • Werk, E.E., jr., Sholiton, L.J., Olinger, C.P.: Amelioration of nontumorous Cushing’s syndrome by diphenylhydantoin. International Congress on Hormonal Steroids, 2nd, Milan, (1966) p. 301 (Excerpta Medica Fndn. New York).

    Google Scholar 

  • Whelton, M.J., Krustev, L.P., Billing, B.H.: Reduction of serum bilirubin by phenobarbital in adult unconjugated hyperbilirubinemia. Is enzyme induction responsible ? Amer. J. Med. 45, 160–164 (1968).

    PubMed  CAS  Google Scholar 

  • Whitehouse, M.W.: Drugs, hormones and other factors influencing steroid and sterol metabolism. In: Lipid Pharmacology, pp. 185–273. Ed. by R. Paoletti. New York: Academic Press 1964.

    Google Scholar 

  • Wurtman, R.J., Axelrod, J., Anton-Tay, F.: Inhibition of the metabolism of H3-melatonin by phenothiazines. J. Pharmacol. exp. Ther. 161, 367–372 (1968).

    PubMed  CAS  Google Scholar 

  • Wynn, J., Gibbs, R., Royster, B.: Thyroxine degradation. I. Study of optimal reaction conditions of a rat liver thyroxine-degrading system. J. biol. Chem. 237, 1892–1897 (1962).

    PubMed  CAS  Google Scholar 

  • Yaffe, S.J., Levy, G., Matsuzawa, T., Baliah, T.: Enhancement of glucuronide conjugating capacity in a hyperbilirubinemic infant due to apparent enzyme induction by phenobarbital. New Engl. J. Med. 275, 1461–1466 (1966).

    PubMed  CAS  Google Scholar 

  • Yates, F.R., Herbst, A.L., Urquhart, J.: Sex differences in rate of ring A reduction of Δ4-3-keto-steroids in vitro by rat liver. Endocrinology 63, 887–902 (1958).

    PubMed  CAS  Google Scholar 

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  1. A. H. Conney
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  2. R. Kuntzman
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  1. Department of Health, Education and Welfare, National Institutes of Health, Bethesda, MD, 20014, USA

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Conney, A.H., Kuntzman, R. (1971). Metabolism of Normal Body Constituents by Drug-Metabolizing Enzymes in Liver Microsomes. In: Brodie, B.B., Gillette, J.R., Ackerman, H.S. (eds) Concepts in Biochemical Pharmacology. Handbook of Experimental Pharmacology / Handbuch der experimentellen Pharmakologie, vol 28 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-65177-9_25

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