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D W Nebert

Publications and source records attributed to D W Nebert.

At least 253 records · Page 14Linked to original sources
PubMed1980

Genetic differences in phenytoin pharmacokinetics. In vivo clearance and in vitro metabolism among inbred strains of mice.

Plasma phenytoin elimination rates were examined among twelve inbred strains of mice. Two populations are identified--the 'fast metabolizers' (BALB/cN, C57BL/6N, C57BL/6J, AKR/N, AKR/J and C3H/HeN) having almost exactly twice as rapid an elimination rate as the 'slow metabolizers' (CL/FR, CBA/J, DBA/2N, STAR/N, SJL/N, DBA/2J and RF/N). The difference in elimination rate between C57BL/6J and DBA/2J cannot be accounted for by dissimilarities in volume of distribution. The phenytoin elimination rate in the (C57BL/6J)(DBA/2J)F1 heterozygote is expressed as an additive trait. A good correlation exists between phenytoin elimination rates in vivo and phenytoin metabolism by liver microsomes in vitro, as determined by a newly described assay using high-performance liquid chromatography. 3-Methylcholanthrene pretreatment does not enhance phenytoin elimination or metabolism. The cytochrome P-450-mediated monoxygenase metabolism of phenytoin is not associated with the Ah locus or with coat color among progeny of the (C57BL/6N)(DBA/2N) F1 x DBA/2N backcross. Phenobarbital pretreatment enhances phenytoin elimination and metabolism in both a fast metabolizer (C57BL/6N) and a slow metabolizer (DBA/2N) strain. Phenobarbital pretreatment probably also induces non-P-450 enzymes, such as those which form the phenytoin dihydrodiol and the glucuronide and glutathione conjugates, in addition to inducing one or more forms of P-450 that oxygenate phenytoin. These data probably reflect allelic differences in a structural gene encoding for one (or more) form(s) of control cytochrome P-450 that metabolizes phenytoin, rather than allelic differences in a regulatory gene. The marked sensitivity of inbred mouse strains CL/FR and A/J and the marked resistance of STAR/N, Swiss-Webster, and C57BL/6 to phenytoin-induced cleft lip and/or palate cannot be explained by genetic differences in phenytoin elimination rates or liver microsomal metabolism in vitro, as measured by the methods described in this report.

Animals↗
PubMed1979

Multiple forms of inducible drug-metabolizing enzymes: a reasonable mechanism by which any organism can cope with adversity.

All organisms possess a number of genetically regulated mechanisms in order to cope with rapid adverse changes in the environment. The two systems which appear to respond to a seemingly endless array of chemical specificities are the immune response and the induction of drug-metabolizing enzymes. Similarities and differences between the immunoglobulin and the cytochrome P-450-mediated monooxygenase systems are described. DNA insertion sequences, plasmid "transposons," maize "controlling elements," gene duplication, intervening sequences, and high-frequency intergenic recombination are all discussed as possible methods by which organisms can "adapt" quickly to a new selective pressure. If the regulation of P-450 induction resembles in any way the other methods by which pro- and eukaryotes cope genetically with numerous forms of environmental adversity, therefore, it is very likely that mammalian tissues contain hundreds, if not thousands, of inducible forms of P-450.

Adaptation, Physiological↗
PubMed1979

The murine Ah locus: in utero toxicity and teratogenesis associated with genetic differences in benzo[a]pyrene metabolism.

Benzo[a]pyrene, at dose between 50 and 300 mg per kg body weight given at Day 7 or 10 of gestation, causes in utero toxicity and teratogenicity more so in genetically "responsive" C57BL/6 than in "nonresponsive" AKR inbred mice. With the use of AKR X (C57BL/6) (AKR)F1 and (C57BL/6) (AKR)F1 X AKR backcrosses, it was shown that allelic differences at the Ah locus in the fetus can be correlated with dysmorphogenesis. If the mother is nonresponsive (Ahd/Ahd), the Ahb/Ahd genotype in the fetus is associated with more stillborns and resorptions, decreased fetal weight, increased congenital anomalies, and enhanced P1-450-mediated covalent binding of BP metabolites to fetal protein and DNA, when compared with the Ahd/Ahd genotype in the fetus from the same uterus. If the mother is responsive (Ahb/Ahd), however, none of these parameters can be distinguished between Ahb/Ahd and Ahd/Ahd individuals in the same uterus, presumably because enhanced BP metabolism in maternal tissues and placenta cancels out these differences between individual fetuses. Of particular interest in our study is the fact that the mother and the father both must be of a particular genotype before differences in teratogenesis among fetuses (due to their genotype) will be expressed. These data might provide an example in attempting to explain clinically why only one child is affected with an apparent "drug-induced syndrome" although the mother has taken the same dose of the particular drug during each of numerous pregnancies.

Abnormalities, Drug-Induced↗
PubMed1979

Pyrolysis products from amino acids and protein: highest mutagenicity requires cytochrome P1-450.

Pyrolysis products of proteins and amino acids are highly mutagenic, but metabolism of these chemicals by rat liver subcellular fractions is known to be required for production of the mutagenic intermediates. We examined the mutagenesis of seven purified pyrolysis products from tryptophan, lysine, glutamic acid, and soybean globulin with Salmonella typhimurium strain TA98 in the presence of liver fractions from genetically "responsive" C57BL/6N and Ah(b)/Ah(d) or "nonresponsive" DBA/2N and Ah(d)/Ah(d) mice that had been pretreated in vivo with benzo[a]pyrene. For all pyrolysis products tested, mutagenesis is 2-fold to more than 1000-fold greater with C57BL/6N and Ah(b)/Ah(d) than with DBA/2N or Ah(d)/Ah(d) liver fractions. A sucrose density gradient assay for detecting the Ah regulatory gene product, the receptor, was studied with C57BL/6N hepatic cytosol. At levels 100 times in excess of [1,6-(3)H]2,3,7,8-tetrachlorodibenzo-p-dioxin, nonlabeled 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, and beta-naphthoflavone (inducers of cytochrome P(1)-450) are able to displace the radioligand from its hepatic cytosolic receptor; four pyrolysates from tryptophan, glutamic acid, and soybean globulin did not have this capacity. These data indicate that the pyrolysis products tested, although not effective as inducers of cytochrome P(1)-450, are most mutagenic when metabolized by P(1)-450. Potent P(1)-450 inducers-present in pyrolysates during the combustion process-might be present in quantities insufficient to initiate mutagenesis or carcinogenesis but might have a synergistic action, or act as "comutagens" or "cocarcinogens," with the N-containing heterocyclic pyrolysis products. A quantitative relationship between mutagenic and carcinogenic potency of these pyrolysis products remains, however, to be demonstrated.

Amino Acids↗
PubMed1979

2,3,7,8-Tetrachlorodibenzo-p-dioxin: covalent binding of reactive metabolic intermediates principally to protein in vitro.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is metabolized by the mouse liver cytochrome P-450-mediated monooxygenase system to reactive intermediates which bind 'covalently' to cellular macromolecules. Although very difficult to quantitate, the presumably covalent binding to microsomal protein occurs between 120 and 2,640 times more readily than binding to deproteinized DNA in the in vitro reaction. Because of the extremely high rate of binding to protein rather than to DNA, it is visualized that TCDD metabolites may be so reactive that they bind in or near the P-450-active site where the TCDD is monoxygenated. This extreme reactivity may preclude the formation of detectable quantities of phenols, dihydrodiols, or conjugated products. The rate of TCDD metabolism is estimated to be between 9,000 and 36,000 times lower than the rate of P-450-mediated benzo[a]pyrene metabolism. To our knowledge, this is the first demonstration that TCDD is metabolized in any organism. There remains the possibility, however unlikely, that this covalently-bound radioactivity represents metabolites of contaminants--present in the radiolabeled TCDD sample in very minute amounts--rather than metabolites of tritiated TCDD itself. The possible relationship between P-450-mediated metabolism of this environmental contaminant and its extreme toxicity or teratogenicity is discussed.

Animals↗