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D R Petersen

Publications and source records attributed to D R Petersen.

At least 55 records · Page 3Linked to original sources
PubMed1987

The oxidation of alpha-beta unsaturated aldehydic products of lipid peroxidation by rat liver aldehyde dehydrogenases.

Lipid peroxidation of microsomal membranes produces a large number of aldehydes, alcohols, and ketones, of which some are cytotoxic. trans-4-Hydroxy-2-nonenal (4HN) and trans-2-hexenal (HX) are two alpha-beta unsaturated aldehydes which are major and minor lipid peroxidation products, respectively. The role of aldehyde dehydrogenase (ALDH) in the oxidation of 4HN and HX was examined using semipurified mitochondrial, cytosolic, and microsomal ALDH isozymes prepared from male Sprague-Dawley rat liver. High- and low- affinity mitochondrial and high-affinity cytosolic ALDH isozymes were able to oxidize 4HN. The affinities of the three isozymes for 4HN, reported as the V/K values, are 0.258, 0.032 and 0.030 nmol NADH formed/min/mg protein/mumol 4HN/liter, respectively. The low-affinity cytosolic and microsomal forms of ALDH are unable to oxidize 4HN. The high-affinity mitochondrial, low-affinity cytosolic, and microsomal ALDH isozymes oxidized HX, displaying V/K values of 0.600, 0.058, and 0.058 nmol NADH formed/min/mg protein/mumol HX/liter, respectively. Oxidation of HX by the low-affinity mitochondrial and high-affinity cytosolic isozyme was not detected. This study indicates that ALDH may participate in the in vivo metabolism of cytotoxic aldehydic products formed during lipid peroxidation.

Aldehyde Dehydrogenase↗
PubMed1987

Accuracy of a 40 dB HL Audioscope and audiometer screening for adults.

This study determined the accuracy of an AudioScope (AS) and pure-tone audiometer (PTA) screening at 40 dB HL from 500 to 4000 Hz in reference to a pure-tone threshold (PTT) test on 1210 ears of adult subjects 20 to 96 yr old. The overall results (averaged over age group and frequency) indicated that the AS and PTA screenings were equally accurate in reference to the PTT test. Averaged over the screening tests, the sensitivity was 91.4% with a false negative rate of 8.6% and the specificity was 93.5% with a false positive rate of 6.5%. As a function of age (averaged over frequency), the AS and PTA screenings had similar accuracy and decreased as age increased to about 60 yr old and then remained stable. As a function of frequency (averaged over age), each screening test had similar accuracy for each frequency. It was concluded that the results of a 40 dB HL AS or PTA screening are very accurate in reference to a PTT test.

Adult↗
PubMed1986

Biochemical genetic variants in mice selectively bred for sensitivity or resistance to ethanol-induced sedation.

The distribution of biochemical genetic variants was examined among eight inbred strains of mice, which served as contributors to a heterogeneous stock of mice (HS), and in short-sleep (SS) and long-sleep (LS) mice, selectively bred from the HS stock for differential ethanol sensitivity. Fifteen loci for enzymes of alcohol and aldehyde metabolism, as well as 12 other biochemical loci, were investigated. Thirteen of these loci exhibited allelic variation between strains, of which six were separately fixed in the SS and LS mice. Comparisons of genetic similarity coefficients, based upon the distributions of allelic variants for the loci examined, with behavioural sensitivities (sleep-time) to an acute dose of ethanol for the inbred and selected strains of mice, indicated no correlations between these data. This suggests that this collective group of loci are not useful indicators of the genes selectively bred in the SS and LS strains, which are responsible for the differential sensitivities to acute doses of ethanol.

Alcohol Dehydrogenase↗
PubMed1985

Effect of tolbutamide and chlorpropamide on acetaldehyde metabolism in two inbred strains of mice.

The mechanisms by which chlorpropamide and tolbutamide disrupt acetaldehyde metabolism were studied in C57BL and DBA mice. Acute po administration of varying doses of tolbutamide or chlorpropamide 2.5 hr before a 3.0 g/kg ip dose of ethanol to C57BL and DBA mice resulted in significant elevations of blood acetaldehyde when measured 2.5 hr after ethanol dosing. Dose-response analysis revealed a significant (p less than .05) difference in ED50 values for the elevated blood acetaldehyde response to tolbutamide in DBA (60 mg/kg) and C57BL (100 mg/kg) mice. The ED50 value for potentiation by chlorpropamide of blood acetaldehyde concentration was similar (23 to 32 mg/kg) in both inbred strains. At higher doses of chlorpropamide, DBA mice displayed elevations of blood acetaldehyde nearly threefold greater than those measured in C57BL mice treated identically. Measurements of aldehyde dehydrogenase (ALDH) in hepatic subcellular fractions, obtained from both inbred strains treated with 100 mg/kg tolbutamide or chlorpropamide prior to a 3.0 g/kg dose of ethanol, revealed a 50 to 80% inhibition of the low-Km ALDH present in mitochondria. Chlorpropamide and tolbutamide did not inhibit ALDH in vitro, suggesting that metabolites of these hypoglycemic agents may be responsible for the genotypic-dependent alterations in in vivo acetaldehyde oxidation.

Acetaldehyde↗
PubMed1985

Isolation and analysis of N-oxide metabolites of tertiary amines: quantitation of nicotine-1'-N-oxide formation in mice.

To investigate the formation and elimination of nicotine-1'-N-oxide (NNO) in mice treated with a single injection of nicotine, sensitive and selective methods were developed to quantitate this polar and heat-labile metabolite. The compound was isolated from tissue homogenates as a dodecyl sulfate ion pair with C18 extraction cartridges and analyzed on an amino bonded-phase high-performance liquid chromatographic column with a mobile phase consisting of isopropanol-water. Overall recoveries of NNO were 64-76% from biological media. Several methods of detection were evaluated; radiolabeling was necessary to achieve the sensitivity required for pharmacokinetic studies in mice. The cis and trans isomers of NNO were separated on a Partisil PAC column and enzymatic selectivity was evaluated for the formation of these isomers in mice.

Animals↗
PubMed1984

Blood and liver acetaldehyde concentrations during ethanol oxidation in C57 and DBA mice.

Hepatic and blood acetaldehyde concentrations during ethanol oxidation were determined in C57 and DBA mice. Liver acetaldehyde was determined with the perchloric acid-thiourea method (no artefactual acetaldehyde formation). Levels ranging from 5 to 118 nmole/g were observed. At ethanol concentrations below 50-60 mumole/g, liver acetaldehyde concentrations were higher in DBA compared with C57 mice. A positive correlation was found between the ethanol and acetaldehyde concentration, when ethanol concentration was below 25 (DBA) or 70 mumole/g (C57). At higher ethanol concentrations the correlations tended to become negative. Artefactual acetaldehyde formation during the analytical procedures was obtained with the use of hemolysis, with or without thiourea, and semicarbazide methods for blood acetaldehyde determination. The magnitude of the artefactually formed acetaldehyde was of such order that no conclusions regarding the existence of true in vivo blood acetaldehyde concentrations could be drawn. Earlier reported mice blood acetaldehyde concentrations are suggested to be re-evaluated.

Acetaldehyde↗
PubMed1983

Pharmacogenetic approaches to the neuropharmacology of ethanol.

The literature cited in this review clearly demonstrates that many of the behavioral and pharmacological responses to either acute or chronic actions of alcohol are indeed heritable. This conclusion is supported by data derived from several different animal models that have been genetically manipulated to display a wide variety of alcohol-related responses. It is doubtful if any one specific animal model will be developed that will serve as a prototype for human alcoholism. When one considers the amount of knowledge resulting from the pharmacogenetic studies reviewed here, it is more likely that major advances in our understanding of alcohol's complex actions will be derived from several different animal models.

Alcohol Drinking↗
PubMed1983

Metabolism of malondialdehyde by rat liver aldehyde dehydrogenase.

Mammalian liver contains a group of pyridine nucleotide linked aldehyde dehydrogenases [E.C. 1.2.1.3] which are present in high specific activity and possess wide substrate specificities. Malondialdehyde (MDA), a difunctional three-carbon aldehyde thought to be toxic, is generated during membrane lipid peroxidation in hepatocytes. The role of aldehyde dehydrogenase (ALDH) in the metabolism of MDA was tested in vitro with subcellular fractions and semipurified cytosolic preparations from rat livers. The cytosolic fraction accounted for virtually all of the MDA (50 microM) metabolizing activity observed in the postnuclear supernatant fraction. The rate of MDA disappearance was relatively low in the mitochondrial fraction and was not detectable in reaction mixtures which contained microsomes. Rat liver cytosol contained two ALDHs with MDA metabolizing activity. These enzymes were separated by DEAE-cellulose ion exchange chromatography and had apparent Km values of 16 microM and 128 microM for malondialdehyde. Mitochondria contained an ALDH enzyme with lower affinity (Km of 7.3 mM with NAD+) for malondialdehyde. These data show that rat liver contains at least three ALDH enzymes which oxidize malondialdehyde.

Aldehyde Dehydrogenase↗
PubMed1983

Time course of the carbon tetrachloride-induced decrease in mitochondrial aldehyde dehydrogenase activity.

Hepatic microsomal enzymes like cytochrome P-450 and glucose 6-phosphatase are inhibited after exposure to CCl4 in vivo. Since comparatively less is known about the effects of CCl4 on nonmicrosomal enzymes, we investigated the rapidity by which CCl4 inhibits the low Km mitochondrial aldehyde dehydrogenase (ALDH) isozyme, an enzyme known to be inhibited 24 hr after CCl4 treatment. The activity of this ALDH isozyme was significantly lowered 6 and 12 hr after a single 1 ml/kg intragastric dose of CCl4. The mitochondrial low Km ALDH specific activities exhibited a similar pattern of destruction/inhibition to the documented target enzyme microsomal cytochrome P-450 in that lowest values were observed 6 hr after CCl4. These values were 44 and 37% of control for cytochrome P-450 content and the low Km ALDH activity, respectively. Alcohol dehydrogenase activity, expressed as activity per gram liver, was depressed 12 hr after CCl4 dosing. Finally, the activity of the low Km cytosolic ALDH, the isozyme that metabolizes malondialdehyde at low concentrations, was not affected by CCl4 treatment. The CCl4-induced decline in the activity of the matrix ALDH isozyme occurs earlier than previously reported mitochondrial damage. The study of sensitive enzymes like the low Km ALDH may provide valuable information by which it may be possible to determine the relationship of the truly rapid biochemical effects of CCl4 such as microsomal lipid peroxidation with later effects on nonmicrosomal components.

Aldehyde Dehydrogenase↗
PubMed1983

Hepatic aldehyde dehydrogenases and lipid peroxidation.

Recent findings have shown that microsomal membrane lipid peroxidation generates a variety of reactive aldehydic products. The interaction of lipid peroxidation products with hepatic aldehyde dehydrogenases (ALDH) was studied using rat liver subcellular fractions. The well-documented membrane peroxidation product malondialdehyde (MDA) was studied to determine if ALDH isozymes play a role in metabolism of this aldehyde. The cytosolic and mitochondrial hepatic subcellular fractions were found to contain ALDH isozymes capable of oxidizing MDA. The kinetic properties of a cytosolic ALDH (Km of approximately 16 microM) suggest that this enzyme may be involved in the metabolism of MDA in vivo. Both the cytosolic and mitochondrial fractions also contained an ALDH isozyme with Km values in the millimolar range. Addition of the cytosolic fraction of rat liver produced a significant decrease in the accumulation of MDA during CCl4-induced microsomal membrane lipid peroxidation but did not protect cytochrome P-450 from destruction. The mitochondrial low Km ALDH isozyme was found to be a target enzyme for inhibition during in vitro microsomal lipid peroxidation. These studies show that a select ALDH isozyme is sensitive to inhibition during membrane lipid peroxidation whereas other isozymes may be involved in the metabolism of aldehydic peroxidation products.

Aldehyde Dehydrogenase↗
PubMed1983

Subcellular distribution and kinetic parameters of HS mouse liver aldehyde dehydrogenase.

1. Aldehyde dehydrogenase subcellular distribution studies were performed in a heterogeneous stock (HS) of male and female mice (Mus musculus) with propionaldehyde (5 mM and 50 microM) and formaldehyde (1 mM) and NAD+ or NADP+. 2. The relative percents of distribution were: cytosolic 55-68%, mitochondrial 12-20%, microsomal 9-18% and lysosomal 3-15% for both propionaldehyde concentrations and NAD+. 3. Kinetic experiments using propionaldehyde and acetaldehyde with NAD+ revealed two separate enzymes, Enzyme I (low Km) and Enzyme II (high Km) in the cytosolic and mitochondrial fractions. 4. The kinetic data also indicated a spectrum of cytosolic low Km values that exhibited a bimodal distribution with one congruent to 40 microM and one congruent to 5 microM. 5. It was concluded that there was no significant difference in aldehyde-metabolizing capability between male and female HS mice, compared on a per gram of liver basis. The cytosolic low Km enzyme plays a major role in aldehyde oxidation at moderate to low aldehyde concentrations.

Aldehyde Dehydrogenase↗
PubMed1983

Selective breeding for a multivariate index of ethanol dependence in mice: results from the first five generations.

Starting with a population of genetically heterogeneous mice (HS/lbg), selection for a multivariate index of the ethanol withdrawal syndrome has been initiated. The study uses within-litter selection to minimize inbreeding and includes replicate high, low, and control lines. After five generations, results indicate that selection is proceeding successfully. There is evidence of asymmetry in the selection, i.e., selection is proceeding more rapidly for signs of severe withdrawal than for mild withdrawal signs. The realized heritability after five generations of within-family selection is approximately 0.15. These selected lines should eventually prove useful in determining some of the underlying genetic, physiological, and biochemical mechanisms involved in ethanol dependence.

Alcohol Drinking↗
PubMed1983

Drug metabolism in isolated proximal tubule cells: aldehyde dehydrogenase.

The mammalian kidney is composed of numerous cell populations associated with the interstitial spaces, vasculature and various portions of the nephron. Not surprisingly, mammalian kidneys also exhibit an array of drug metabolizing activities, including the pyridine nucleotide-linked aldehyde dehydrogenase(s) (ALDH). To define the ALDH activity in segment 2 of the proximal tubule, a portion of the nephron which frequently shows drug-induced pathology, proximal tubules were isolated by purely mechanical methods from female rabbits. Isopycnic centrifugation of tubule-derived postnuclear supernates in linear sucrose gradients resulted in propionaldehyde (5 mM)-driven ALDH activity being distributed in a manner consistent with both a mitochondrial and cytosolic localization. Mitochondrial and cystosolic fractions yielded biphasic reciprocal plots when propionaldehyde was used as substrate. Km values of 282 microM and 4 mM were obtained from the mitochondrial enzymes, whereas the cytosolic enzymes gave KmS of 132 microM and 2.4 mM. The apparent Vmax values (nanomoles of NADH produced per minute per milligram of protein) are 16.3 and 37.8 for the mitochondrial enzymes and 23.5 and 19.0 for the cytosolic enzymes. Thus, the S2 proximal tubule cells contain ALDH activities at levels and subcellular sites comparable to those found in the liver. Because the proximal tubules constitute approximately 40% of the renal cortical mass, the high levels of ALDH activity observed in these cells may protect other cortical cells and more distal nephron components by detoxifying potentially cytotoxic aldehydes.

Aldehyde Dehydrogenase↗
PubMed1982

Analyses of nicotine and cotinine in tissues by capillary gas chromatography and gas chromatography-mass spectrometry.

Selective extraction and chromatographic techniques have been developed to measure low nanogram quantities of nicotine and cotinine in tissues. Analyses were performed by capillary column gas chromatography with a specific nitrogen-phosphorus detector and by gas chromatography-mass spectrometry. With close structural analogues for internal standards, high quantitative accuracy and precision were demonstrated for the range 5-1000 ng per g of tissue. The sensitivity limit was 2-3 ng/g for both compounds. The advantage of these techniques compared to previously published methods is increased selectivity; the other methods were developed for analysis of biological fluids and are not readily adaptable to more complex biological matrices such as tissue homogenates. With the newly developed techniques, we were able to perform a pharmacokinetic study of nicotine and cotinine in mouse liver following a single intraperitoneal injection of nicotine.

Animals↗
PubMed1982

An overview of the genetics of psychopathology.

The suggestion that psychopathologies are in part mediated by aberrant catecholamine metabolism has resulted in one of the more rapidly growing areas of pharmacogenetics. Collectively, the studies conducted to date indicate that psychopathological conditions have multiple causes which cannot be related to single genetic or biochemical deficits. However, through multidisciplinary research integrating behavioral, genetic, and biochemical approaches, a great deal of insight may be gained concerning the causes of psychopathological disorders and the use of drug therapy to modify the course of these illnesses.

Animals↗
PubMed1982

Ethanol elimination rates in mice: effects of gender, nutrition, and chronic ethanol treatment.

Twenty male and 20 female mice of a heterogeneous stock were assigned to each of three groups. One groups was administered ethanol in a liquid diet for 9 days, a second group was fed an isocalorically controlled diet containing no ethanol for the same length of time, and the third group was fed standard lab chow. Each animal was injected with a dose of ethanol equal to 3.5 g/kg body weight at the time corresponding to 6 hr post-withdrawal for the ethanol-treated group. Blood ethanol elimination rates were determined at 1, 2, and 3 hr post-injection. Neither gender, nutritional state, nor chronic ethanol treatment was found to affect ethanol elimination rates.

Animals↗