S R Michener

Research Triangle Park Laboratories, Inc., Raleigh, North Carolina, United States

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Publications (10)37.27 Total impact

  • D E Chapman, S R Michener, G Powis
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    ABSTRACT: The relationships between nucleotide (ATP, ADP, AMP, NADPH, NADP(+), NADH and NAD(+)) concentrations and the metabolism of the hepatocarcinogen 2,6-dinitrotoluene (2,6-DNT) in cultured slices of rat liver were investigated. ATP, NADPH and NADH concentrations in freshly prepared rat liver slices at the beginning of culture were 48-67% lower than those measured in freeze-clamped rat liver (in vivo values). ATP concentrations in cultured liver slices increased with time of incubation, and after 4 hr ATP concentrations in liver slices were 25% greater than in vivo values. In contrast, NADPH and NADH concentrations did not recover with time of culture, and after 4 hr NADPH and NADH concentrations in liver slices were 50 and 24% of in vivo values, respectively. The addition of ethanol (50 mm) to cultured liver slices increased NADH concentrations by 132%, relative to untreated liver slices. Treatment of liver slices with ammonium chloride (10 mm), 6-aminonicotinamide (1 mm), or the substitution of fructose for glucose in the incubation medium significantly decreased NADPH concentrations by 64, 44 and 63%, respectively. All treatments significantly decreased ATP concentrations; fructose was the most effective agent tested and decreased liver slice ATP concentrations by 69%. These results indicate that the changes in liver slice nucleotide concentrations that occur during culture are not irreversible, and we suggest that these changes are a homoeostatic response to culture conditions and not a reflection of tissue damage or cytotoxicity. Rates of 2,6-dinitrotoluene metabolism by rat liver slices were unaffected by fructose or ammonium chloride, despite the decrease in NADPH concentrations produced by these agents. These results suggest that NADPH concentrations are not rate-limiting to 2,6-DNT metabolism by rat liver slices.
    Toxicology in Vitro 06/1994; 8(3):343-9. · 2.65 Impact Factor
  • D E Chapman, S R Michener, G Powis
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    ABSTRACT: Liver slice tissue culture was used to compare human and rat liver metabolism of 2,6-dinitrotoluene (2,6-DNT). Oxidative metabolism of the 2,6-DNT side-chain methyl moiety produced 2,6-dinitrobenzylalcohol and the glucuronide conjugate of 2,6-dinitrobenzylalcohol, and reductive metabolism of the 2,6-DNT nitro groups produced 2-amino-6-nitrotoluene. Metabolites derived from side-chain oxidation accounted for 90-95% of the 2,6-DNT metabolites produced by rat liver slices under ambient oxygen concentrations of 25-100%; however, under 0% oxygen (100% nitrogen) atmospheres 2-amino-6-nitrotoluene accounted for 96% of the total metabolites. An increase in slice thickness from 0.3 to 0.8 mm decreased the ratio of oxidized to reduced 2,6-DNT metabolites produced by rat liver from 9:1 to 1:1. Under 100% oxygen and in liver slices approximately 0.3 mm thick, average rates of 2,6-DNT oxidative metabolism by human (five subjects) and rat liver were 1.0 and 2.1 nmol/min/g liver, respectively. K(m) and V(max) for the oxidative metabolism of 2,6-DNT by rat liver slices were 0.38 mm and 12 nmol/min/g liver, respectively. The average K(m) and V(max) for the oxidative metabolism of 2,6-DNT by two human subjects were 0.019 mm and 0.91 nmol/min/g liver, respectively.
    Toxicology in Vitro 05/1993; 7(3):213-20. · 2.65 Impact Factor
  • D E Chapman, S R Michener, G Powis
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    ABSTRACT: 1. 2,6-Dinitrotoluene (2,6-DNT) metabolism by human liver and male Fischer F344 rat liver subcellular fractions under aerobic (100% oxygen) and anaerobic (100% nitrogen) incubation conditions was examined. Under aerobic conditions the major 2,6-DNT metabolite formed by hepatic microsomes was 2,6-dinitrobenzyl alcohol (2,6-DNBalc); under anaerobic conditions 2-amino-6-nitrotoluene (2Am6NT) was the major metabolite. 2. Rates of 2,6-DNBalc formation by human and rat liver microsomes under aerobic conditions were 247 and 132 pmol/min per mg protein, respectively. Rates of 2Am6NT formation by human and rat liver microsomes under anaerobic conditions were 292 and 285 pmol/min per mg protein, respectively. Anaerobic reduction of 2,6-DNT to 2Am6NT by rat and human liver microsomes was inhibited by carbon monoxide and metyrapone, which indicates that microsomal metabolism of 2,6-DNT to 2Am6NT is mediated by cytochrome P-450. 3. Liver cytosolic fractions also metabolized 2,6-DNT to 2Am6NT under anaerobic conditions. Formation of 2Am6NT by human and rat liver cytosols was supported by hypoxanthine, NADPH and NADH. Allopurinol inhibited the hypoxanthine-supported anaerobic metabolism of 2,6-DNT by rat, but not human, liver cytosol. Dicumarol inhibited the NADPH-supported anaerobic metabolism of 2,6-DNT by human, but not rat, liver cytosol. These results indicate that xanthine oxidase contributes to the hypoxanthine-supported anaerobic metabolism of 2,6-DNT by human liver cytosol.
    Xenobiotica 09/1992; 22(8):1015-28. · 1.98 Impact Factor
  • D E Chapman, S R Michener, G Powis
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    ABSTRACT: Previous studies indicate that tris(2-chloroethyl)phosphate (TCP) preferentially produces hippocampal brain lesions in female versus male rats, and the expression of these lesions is inversely related to the in vivo rate of TCP metabolism. In the present studies, TCP (0.17 mM in all incubations) was metabolized in vitro by liver slices and microsomes from human and Fischer 344N rat liver to bis(2-chloroethyl) hydrogen phosphate (BCP), 2-chloroethanol (CE), and three unidentified metabolites. The rate of TCP metabolism by male rat liver microsomes and liver slices was 0.049 nmol/min/mg protein and 2.53 nmol/min/g liver, respectively. TCP metabolism by male rat liver microsomes was inhibited by 10 microM diisopropyl fluorophosphate, 10 microM paraoxon and carbon monoxide. TCP did not appear to be metabolized by female rat liver microsomes, but female rat liver slices metabolized TCP at a rate of 1.51 nmol/min/g liver. TCP was metabolized by male and female rat plasma at a rate of 0.156 and 0.169 nmol/ml plasma, respectively. TCP was metabolized by male and female human liver microsomes at a rate of 0.027 and 0.031 nmol/min/mg protein, respectively. TCP was metabolized by male and female human liver slices at a rate of 1.37 and 1.82 nmol/min/g liver, respectively. BCP and CE were the major metabolites formed in all studies, except for liver slices and microsomes from two human male subjects in which an unidentified metabolite constituted 29 to 38% of the total TCP metabolism. TCP was not metabolized by plasma or whole blood from male or female human subjects. These results support the previously reported sex-specific difference in TCP metabolism by male and female Fischer 344N rats. However, no sex-specific difference in rates of TCP metabolism by male and female human liver microsomes or slices was observed.
    Fundamental and Applied Toxicology 09/1991; 17(2):215-24.
  • T R Koch, S R Michener, V L Go
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    ABSTRACT: Determination of plasma levels of vasoactive intestinal polypeptide (VIP) has been used for screening patients with chronic diarrhea to identify potential neuroendocrine tumors. This 6-year blinded study from 1981 to 1986 examines the causes of elevated VIP levels in patients. In healthy volunteers ( n = 144), VIP concentrations ranged from 14 to 76 pg/mL (mean +/- SE, 28 +/- 12), whereas in chronic renal failure, 4 of 34 patients or 12% [serum creatinine 4.5 - 9.0 mg/dL (397-795 mumols/L)] had an elevation to greater than 100 pg/mL. No patient with idiopathic hepatic cirrhosis (n = 12) had elevation of serum concentration of this peptide. Among 588 consecutive unselected patients undergoing evaluation for chronic diarrhea (n = 362; 62%) or possible neuroendocrine tumor (n = 214; 36%), 23 patients (3.9%) had concentrations greater than 76 pg/mL. In this group, 5 patients had functioning (VIP, 160-5975 pg/mL) and 5 had nonfunctioning (VIP, 80-120 pg/mL) pancreatic islet cell carcinomas: all 10 patients had hepatic metastases. Other known cases of elevated levels of VIP, ranging from 80 to 340 pg/mL, included other neurogenic tumors (n = 3), small- bowel resection (n = 2), inflammatory bowel disease (n = 2), chronic renal failure (n = 1), and prolonged fasting (n = 1). Patients with diarrhea in which VIP-secreting tumors were identified had plasma vasoactive intestinal peptide concentrations greater than 140 pg/mL. In patients with chronic diarrhea, determination of plasma vasoactive intestinal peptide levels did identify tumors secreting this peptide, but the results from this referral institution did not show identification of these tumors early in their clinical course.
    Gastroenterology 02/1991; 100(1):99-106. · 12.82 Impact Factor
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    C L Berseth, S R Michener, C K Nordyke, V L Go
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    ABSTRACT: Concentrations of gastrointestinal neuropeptides in serial human milk samples from 28 women were determined over the first 6 postpartum mo. All gut neuropeptides were present during the first postpartum week. Gastric inhibitory peptide (GIP) concentration remained constant but the others decreased by 6 wk. Bombesin concentration in breast milk was threefold greater than concurrent plasma concentration (p less than 0.001); all other neuropeptides were at the same or lower concentrations in milk than in plasma. At 36 wk gestation plasma concentrations of GIP were lower and concentrations of vasoactive intestinal peptide were higher than concentrations in age-matched control subjects. Concentrations of gastrin and cholecystokinin, bombesin, peptide histidine methionine, peptide YY, and neurotensin in plasma were similar in pregnant and nonpregnant women. These gut neuropeptides in milk may be important for growth and maturation of the gastrointestinal system in neonates. Bombesin may contribute to neonatal hypergastrinemia.
    American Journal of Clinical Nutrition 07/1990; 51(6):985-90. · 6.50 Impact Factor
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    ABSTRACT: The distribution of galanin-like immunoreactivity in various regions of the central nervous system was assessed in three mammalian species, pig, rat, and human, by radioimmunoassay. Galanin concentrations were highest in the hypothalamus and pituitary region. In spinal cord, there was a rostrocaudal/dorsoventral gradient with highest levels observed in the sacral dorsal horn. Serial dilutions of porcine tissue extracts diluted parallel to the porcine standard curve, while the rat and human tissue extracts did not. In all tissues examined by high pressure liquid chromatography, the principal peak of immunoreactivity coeluted with the authentic porcine galanin standard and was decreased by trypsin cleavage. These results suggest a role for galanin in the central nervous system and support species differences in the structure of galanin.
    Peptides 01/1990; · 2.52 Impact Factor
  • T R Koch, S R Michener, J A Carney, V L Go
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    ABSTRACT: The sequence for peptide histidine-methionine is present within the same preprohormone as vasoactive intestinal polypeptide. Since our previous study using radioimmunoassay had demonstrated significantly decreased colonic concentrations of vasoactive intestinal polypeptide in ulcerative colitis and Crohn's colitis compared to normal colon, we determined the distribution and quantitation of peptide histidine-methionine. Fresh surgical specimens were dissected into mucosal-submucosal and muscularis externa layers prior to acid extraction and specific radioimmunoassay. One immunoreactive species that appeared to coelute with peptide histidine-methionine was separated by reverse-phase high-performance liquid chromatography. Mucosal-submucosal concentrations of peptide histidine-methionine were significantly decreased in ulcerative colitis and Crohn's colitis, compared to those in normal colon. In normal ileum and colon, linear correlation analysis showed no relationship between patient age and tissue concentrations of peptide histidine-methionine. However, a parallel decrease in molar concentrations of peptide histidine-methionine and vasoactive intestinal polypeptide in ulcerative colitis and Crohn's colitis was demonstrated by linear correlation analysis. These results are consistent with the hypothesis that peptide histidine-methionine and vasoactive intestinal polypeptide are colocalized within the same neural structures that have been altered in the idiopathic inflammatory bowel diseases.
    Digestive Diseases and Sciences 05/1988; 33(4):423-8. · 2.26 Impact Factor
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    ABSTRACT: Levels of substance P (sP), peptide-histidine-isoleucine (PHI), vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), neurotensin (NT), bombesin (BOM) and methionine-enkephalin (Met-Enk) like immunoreactivity were measured in cat, dog, primate and sloth cervical, thoracic, lumbar and sacral dorsal and ventral horns and dorsal root ganglia. The levels of peptides in the cat sacral cord and the principal peaks of immunoreactivity on a 10-60% acetonitrile gradient on a C18 reverse phase high performance liquid chromatography (HPLC) were sP (sP1-11: 369 ng/g), PHI (PHI: 271 ng/g), VIP (VIP1-28: 210 ng/g), Met-Enk (Met1-5 and extended forms: 257 ng/g), BOM (BOM1-10 and GRP1-27: 20 ng/g), CCK (CCK-8: 15 ng/g) and NT (NT1-13: 10 ng/g). Consideration of the rostrocaudal levels revealed an approximately even distribution with the exception of VIP and PHI which showed sacral/cervical ratios of 79 and 63. For sP, Met-Enk and BOM dorsal/ventral ratios were greater than 1 at all spinal levels. For VIP, PHI and CCK these ratios were greater than 1 only in the sacral cord. Dorsal root ganglion (DRG) levels of sP, VIP, PHI were readily measurable in single ganglia and covaried with the respective levels in the dorsal cord. Pooled samples of spinal ganglia and the trigeminal ganglia revealed that the relative levels of peptide immunoreactivity were: sP (25 ng/g); VIP (26 ng/g); PHI (28 ng/g); Met-Enk (6 ng/g); CCK (2 ng/g); NT (1 ng/g); and BOM (1 ng/g).
    Peptides 01/1988; 9(2):357-72. · 2.52 Impact Factor
  • D E Chapman, T J Moore, S R Michener, G Powis
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    ABSTRACT: The in vitro metabolism of [14C]toluene by liver microsomes and liver slices from male Fischer F344 rats and human subjects has been compared. Rat liver microsomes produced only benzyl alcohol from toluene. Liver microsomes from human subjects metabolized toluene to benzyl alcohol, benzaldehyde, and benzoic acid. Liver microsomes from one human donor also produced p-cresol and o-cresol. The overall rate of toluene metabolism by human liver microsomes was 9-fold greater than by rat liver microsomes. Human liver microsomal metabolism of benzyl alcohol to benzaldehyde required NADPH and was inhibited by carbon monoxide and high pH (pH 10). but was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P-450, rather than alcohol dehydrogenase, was responsible for the metabolism of benzyl alcohol to benzaldehyde. Human and rat liver slices metabolized toluene to hippuric acid and benzoic acid. The overall rate of toluene metabolism by human liver slices was 1.3-fold greater than by rat liver slices. Cresols and cresol conjugates were not detected in human or rat liver slice incubations. Covalent binding of [14C]toluene to human liver microsomes and slices was 21-fold and 4-fold greater than to the comparable rat liver preparations. Covalent binding did not occur in the absence of NADPH, was significantly decreased by coincubation with cysteine, glutathione, or superoxide dismutase, and was unaffected by coincubation with lysine. Protease and ribonuclease digestion decreased the amount of toluene covalently bound to human liver microsomes by 78% and 27% respectively. Acid washing of human liver microsomes had no effect on covalent binding.(ABSTRACT TRUNCATED AT 250 WORDS)
    Drug Metabolism and Disposition 18(6):929-36. · 3.36 Impact Factor

Publication Stats

123 Citations
37.27 Total Impact Points

Institutions

  • 1994
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 1988–1994
    • Mayo Clinic - Rochester
      • Department of Surgery
      Rochester, Minnesota, United States
  • 1993
    • University of Washington Seattle
      • Department of Pharmacology
      Seattle, WA, United States
  • 1990–1992
    • Mayo Foundation for Medical Education and Research
      • • Department of Pharmacology
      • • Department of Pediatrics
      Scottsdale, AZ, United States