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1.
J Nutr ; 122(1): 74-81, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1729474

ABSTRACT

The effects of selenium, vitamin E, and DL-methionine deficiency on the acute lethality and hepatotoxicity of acetaminophen in male CD-1 mice were studied. Vitamin E and selenium deficiencies led to an increase in the acute lethality of acetaminophen, with a decrease in the LD50 from 376 to 84 mg/kg. These dietary deficiencies impaired the inducibility of the hepatic microsomal mixed function oxidase system by phenobarbital, but on the basis of the covalent binding of acetaminophen to microsomes, these treatments did not alter the activation of acetaminophen to a reactive intermediate by this system. Addition of methionine to the deficient diet restored hepatic glutathione content to control levels but did little to protect against the acute lethality of acetaminophen. In methionine-supplemented animals, the addition of either selenium or vitamin E increased the LD50 of acetaminophen to 167 and 200 mg/kg, respectively. Administration of a sublethal, toxic dose of acetaminophen (LD30) to the methionine-supplemented and selenium- and vitamin E-deficient mice did not produce any hepatic damage as evidenced by a lack of plasma aminotransferase elevation. In view of the known antioxidant effects of vitamin E and selenium, these data suggest the involvement of a reactive radical in the acute lethality of acetaminophen and further suggest that death from acute acetaminophen overdose in chronic selenium- and vitamin E-deficient mice may be unrelated to liver necrosis.


Subject(s)
Acetaminophen/toxicity , Liver/drug effects , Selenium/deficiency , Vitamin E Deficiency/metabolism , Animals , Body Weight , Drug Synergism , Lethal Dose 50 , Liver/enzymology , Liver/metabolism , Male , Methionine/deficiency , Mice , Mixed Function Oxygenases/metabolism
2.
J Med Chem ; 26(10): 1343-8, 1983 Oct.
Article in English | MEDLINE | ID: mdl-6620295

ABSTRACT

A series of 3-O-alkylmorphine analogues was synthesized to determine if there was a good correlation between the rate of metabolism, type I binding affinity, and lipid solubility. The data indicate that the Km for the N-demethylation declines with increasing chain length from C1 to C9, while for increasing chain length the Vmax for the N-demethylation increases to a maximum of 15.20 nmol min-1 (mg of protein)-1 for the butyl analogue (C4) and then slowly declines with analogues with chain lengths greater than butyl (C4). The decyl (C10) and dodecyl (C12) analogues showed no activity. There was a good correlation between the lipophilicity and Km values, except for codeine and the C10 and C12 analogues. The type I binding dissociation constants (Ks) also decreased with increasing alkyl chain length with an excellent correlation between the Ks and log P. The ODmax did not change with increasing the chain length of the analogues. Our data suggest that in male rat hepatic microsomes the catalytic site for N-demethylation and the site for type I binding in this series of compounds are similar but distinct.


Subject(s)
Microsomes, Liver/enzymology , Morphine Derivatives , Oxidoreductases, N-Demethylating/metabolism , Alkylation , Animals , Kinetics , Male , Morphine/metabolism , Morphine/pharmacology , Rats , Structure-Activity Relationship , Substrate Specificity
3.
Drug Metab Dispos ; 11(5): 477-80, 1983.
Article in English | MEDLINE | ID: mdl-6138234

ABSTRACT

We have modified our radiometric assay for ethylmorphine N-demethylase to examine the metabolism of codeine. We find that the current assay gives excellent separation of metabolites with a zero time activity of 0.08%. The N- and O-demethylations are linear for up to 30 min with up to 1 mg/ml of microsomal protein. The pH profiles show slightly different maxima (N-demethylation, pH 8.0; O-demethylation, pH 7.8). The kinetic parameters for N-demethylation were markedly higher (Vmax = 5.6 nmol/min/mg protein; KM = 714 microM) than those for O-demethylase (Vmax = 0.75 nmol/min/mg protein; KM = 149 microM). These data suggest that the HCHO results primarily from the N-demethylase. Further, the differences in the kinetic parameters and the pH profile suggest that these two activities are catalyzed by different enzymatic systems.


Subject(s)
Codeine/metabolism , Animals , Dealkylation , In Vitro Techniques , Liver/metabolism , Male , Rats , Rats, Inbred Strains , Time Factors
4.
Biochem Pharmacol ; 32(1): 91-6, 1983 Jan 01.
Article in English | MEDLINE | ID: mdl-6830622

ABSTRACT

Studies were carried out to characterize the response of hepatic mixed function oxidase (MFO) activity to chronic ascorbic acid deficiency and excessive ascorbic acid intake in the guinea pig. When guinea pigs were fed excessive ascorbic acid, there was a small increase in hepatic cytochrome P-450 which was unaccompanied by any alteration in drug-metabolizing enzyme activity. Similarly, induction of MFO activity by phenobarbital was not modified by excessive ascorbic acid administration. Chronic ascorbic acid deficiency resulted in depressed metabolism of aniline, aminopyrine, ethoxycoumarin and benzphetamine, but not of ethylmorphine, in comparison with animals fed diets containing control and/or excessive amounts of ascorbic acid. In contrast to the metabolism of all drugs studied, the 7 alpha-hydroxylation of cholesterol was depressed by both inadequate and excessive vitamin C intake, demonstrating the unique sensitivity of cholesterol 7 alpha-hydroxylase to dietary ascorbate.


Subject(s)
Ascorbic Acid/pharmacology , Liver/enzymology , Mixed Function Oxygenases/metabolism , Oxidoreductases/metabolism , Animals , Ascorbic Acid Deficiency/enzymology , Benzphetamine/metabolism , Cytochrome P-450 Enzyme System/metabolism , Diet , Dose-Response Relationship, Drug , Enzyme Induction/drug effects , Guinea Pigs , Kinetics , Male , Phenobarbital/pharmacology
8.
J Pharmacol Exp Ther ; 211(1): 213-8, 1979 Oct.
Article in English | MEDLINE | ID: mdl-490320

ABSTRACT

A sensitive and convenient radioassay for the in vitro determination of ethylmorphine N-demethylase and O-de-ethylase activity has been developed. Ethylmorphine[6-3H] was prepared by reduction of the corresponding morphinone in nearly quantitative yield. After incubation with hepatic microsomes from male rats, the reaction was terminated by the addition of 5 ml of acetone. The sample was saturated with potassium acetate and extracted twice with acetone giving complete extraction of the radiolabeled ethylmorphine and its metabolites. After the combined organic phases were evaporated, the samples were dissolved in methanol and applied to a Silica Gel GF plate with subsequent development in ethyl acetate-methanol-concentrated NH4OH. The amount of radioactivity detected for the morphine and norethylmorphine bands at zero time was approximately 0.05% of the original amount of labeled ethylmorphine added to the incubation media. Similarly, the Km values were 52 and 250 microns for the O- and N-dealkylation respectively, while the Vmax values were 5.0 and 1.8 nmol/mg of protein per min. Finally, with this assay we have observed constant specific activity for both the N- and O-dealkylation of ethylmorphine[6-3H] with as little as 10 micrograms of microsomal protein per ml of incubation media.


Subject(s)
Ethylmorphine-N-Demethylase/metabolism , Ethylmorphine/metabolism , Microsomes, Liver/enzymology , Morphine Derivatives/metabolism , Oxidoreductases, N-Demethylating/metabolism , Oxidoreductases/metabolism , Animals , Dealkylation , Ethylmorphine/isolation & purification , In Vitro Techniques , Kinetics , Male , Methods , Rats , Tritium
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