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D R Petersen

Publications and source records attributed to D R Petersen.

At least 73 records · Page 4Linked to original sources
PubMed1982

Inhibition of mitochondrial aldehyde dehydrogenase by malondialdehyde.

Rat liver mitochondria contain an aldehyde dehydrogenase (ALDH, EC 1.2.1.3) with a low Km for acetaldehyde (2 microM) which is susceptible to inhibition by a variety of agents including p-chloromercuribenzoate and arsenite. This low Km ALDH isozyme has been shown to be decreased in activity following CCl4 treatment in vivo and by lipid peroxidation in vitro. Malondialdehyde, the most studied product of lipid peroxidation, was investigated for possible inhibitory effects on the low Km ALDH for rat liver mitochondria. Malondialdehyde was found to be a potent inhibitor of the enzyme. The enzyme was equally sensitive to inhibition when intact mitochondrial preparations were compared with disrupted mitochondria. The extent of enzyme inhibition was dependent on malondialdehyde concentration and time of incubation. High concentrations of malondialdehyde completely inhibited low Km mitochondrial ALDH activity. Malondialdehyde was found to inhibit the low Km ALDH irreversibly. The rate of ALDH inactivation exhibited two phases, one a rapid rate phase (5-15 s) and a second slower rate phase, both of which showed rates which were dependent on malondialdehyde concentration. These data show that malondialdehyde is a potent, high affinity, irreversible inhibitor of the low Km ALDH of rat liver mitochondria. This ALDH isozyme is considered to be the most important enzyme in acetaldehyde metabolism. Malondialdehyde inhibition of the low Km ALDH may be important since both ethanol and acetaldehyde are thought to stimulate hepatic lipid peroxidation.

Aldehyde Dehydrogenase↗
PubMed1982

Studies on carbon tetrachloride-ethanol interactions in mice.

Male C57BL/6J (C57) and DBA/2J (DBA) inbred mice were dosed with either corn oil or carbon tetrachloride (CCl4) in corn oil 24 h before a 3.25 g/kg i.p. dose of ethanol. The CCl4 doses were increased in approximate half-log intervals (5, 15, 50, 150 or 500 microliter/kg, intragastrically (i.g.)). Blood acetaldehyde concentrations were significantly increased 1, 2, 3 and 4 h after ethanol administration at CCl4 doses of 15 microliter/kg and higher, with DBA and C57 mice exhibiting similar dose-response effects up to the 150 microliter/kg dose. A CCL4 dose of 500 microliter/kg produced differences in blood acetaldehyde elevation between the two inbred strains (DBA - 5-fold, C57 - 3-fold). Associated with the elevation of blood acetaldehyde content was a decrease in the rat of elimination of ethanol from blood. Using male genetically heterogeneous stock (HS) mice it was shown that phenobarbital pretreatment potentiated the CCl4-induced decrease in in vivo acetaldehyde oxidation. An equimolar dose of CHCl3 (0.5 mmol/kg) was without effect in either control or phenobarbital-pretreated mice. Mice pretreated with 0.5 mmol/kg, i.g., 1,2-dichloroethane, 1, 1,2-trichloroethylene or bromobenzene did not exhibit significant interaction with ethanol. These data show that in vivo acetaldehyde oxidation is inhibited by very low doses of CCl4 (15 microliter/kg, i.g.) and that this inhibition is enhanced by the cytochrome P-450-inducing agent phenobarbital.

Acetaldehyde↗
PubMed1982

Metabolic interactions of aldehyde dehydrogenase with therapeutic and toxic agents.

The specific physiological roles of ALDH have not been determined. In this overview, we have identified malondialdehyde as one potential endogenous toxic aldehyde that is oxidized by ALDH. Undoubtedly, there are other cytotoxic aldehydes which occur in several different tissues that are detoxified by this same system of enzymes. Intuitively, the role of aldehyde dehydrogenases in the detoxification of xenobiotic aldehydes should also receive additional consideration and attention. An interesting feature of specific studies described in this overview is that a single aldehydic substrate, like malondialdehyde, may be a substrate for one ALDH isozyme and a potent inhibitor of ALDH present in another cellular compartment. Assuming that the ALDH susceptible to this inhibition performs other important physiological or biochemical functions, a potentiating effect would occur. Thus, the efficient metabolism of potentially cytotoxic aldehydes may be a protective mechanism against a number of different organ system pathologies. Another striking feature of ALDH is its sensitivity to in vitro and in vivo inhibition by a number of chemically and pharmacologically diverse agents. This characteristic suggests that ALDH may be a target enzyme for inhibition by several therapeutically important drugs or their metabolites. As a result, the perturbation of ALDH by specific therapeutic agents suggests a potential role of this enzyme in a number of different drug-induced toxicities.

Alcohol Oxidoreductases↗
PubMed1982

Selective breeding in mice for severity of the ethanol withdrawal syndrome.

Starting with a foundation population of 200 genetically heterogeneous mice (HS/Ibg), selective breeding has been initiated for a multivariate index of the ethanol withdrawal syndrome. This paper discusses the advantages of using multivariate indices to define pharmacological concepts. The seven variables included in our multivariate index are described. Because five of the seven variables showed a significant sex difference, separate principal component analyses were performed to establish selection indices appropriate for each sex. The study employs within-family mating to minimize inbreeding and includes replicate high, low, and control lines. These selectively bred lines should eventually provide a useful animal model for studying physiological and neurological mechanisms that may be involved in the ethanol withdrawal syndrome.

Alcohol Withdrawal Delirium↗
PubMed1982

Increase in hepatic microsomal ethanol oxidation by a single dose of ethanol.

A single injection of ethanol was shown to produce a relatively rapid increase in the in vitro activity of aniline hydroxylase and in microsomal ethanol oxidation. Stimulation of the microsomal ethanol oxidating system (MEOS) was dependent on the ethanol dose and time after dosing. Hepatic MEOS activities were significantly increased 2, 3 and 4 hr after a single 4.0 g/kg i.p. dose of ethanol and 4 hr after administration of 2.0 and 3.25 g/kg doses. Renal MEOS activity was also significantly increased 4 hr after a 4.0 g/kg dose of ethanol. Hepatic MEOS and aniline hydroxylase activities per gram of liver were significantly increased 2 hr after a 4.0 g/kg dose of ethanol, whereas microsomal cytochromes P-450 and b5, NADPH cytochrome c reductase, protein and NADPH-stimulated and ethanol/NADPH-stimulated lipid peroxidation were unchanged. Cycloheximide pretreatment did not block ethanol-induced stimulation of aniline hydroxylase or MEOS activity. Finally, an acute injection of ethanol (4.0 g/kg) produced significantly higher MEOS activities per gram of liver (121% of control) in mice chronically ingesting ethanol than in mice treated with saline. This investigation shows that MEOS activity can respond rapidly to a dose of ethanol and that synthesis of new protein is not responsible for this stimulation of activity.

Aniline Hydroxylase↗
PubMed1981

The effects of chronic ethanol ingestion on ethanol binding to hepatic cytochrome P-450 and on certain hepatic and renal parameters in the "long sleep" and "short sleep" mouse.

Male mice selected for genetic differences in ethanol-induced sleep time, thereby designated long sleep (LS) an short sleep (SS), were treated with the Lieber-DeCarli liquid diet for 25 days. This chronic ethanol treatment produced an increase in liver/body weight and kidney/body weight in SS mice only. In addition, chronic ethanol treatment produced significant increases in both LS and SS treated mice in in vivo ethanol elimination, hepatic cytochromes P-450 and B5, NADPH cytochrome c reductase and hepatic and renal 7-ethoxycoumarin O-de-ethylase activity. Genotypic differences were observed in the magnitude of response of microsomal ethanol oxidation per mg of microsomal protein (SS greater than LS). Further, control LS and SS mice possessed substantially different activity of renal 7-ethoxycoumarin O-de-ethylase. Both lines exhibited similar induced renal 7-ethoxycoumarin O-de-ethylase activity after chronic ethanol ingestion. Ethanol binding spectra produced when ethanol was added to hepatic microsomes were examined using double reciprocal plots. Chronic ethanol ingestion produced genotypically related (LS greater than SS) increases in the absorbance change maximum per mg of microsomal protein. No significant changes in the spectral dissociation constant or absorbance change maximum per nM cytochrome P-450 were observed following ethanol treatment.

Alcoholism↗
PubMed1981

Liver cytosolic aldehyde dehydrogenase activity in the pregnant mouse.

A 3-fold increase in aldehyde dehydrogenase (A1DH) was found in the cytosolic fraction of mouse liver homogenates during pregnancy. The increase in A1DH activity began at day 10 of pregnancy, peaked at parturition, and declined in a biphasic manner with half-lives of 4.15 and 47.7 days. Enzymes from control (beta A1DH), pregnant (pi A1DH) and phenobarbital-treated (phi AlDH) were partially purified and compared. All had molecular weights of approximately 60,000 daltons. Substrate specificities were similar except that phi A1DH had a lower Km for propionaldehyde than beta or pi and both pi and phi oxidized 4-carboxybenzaldehyde poorly compared to beta. Electrophoretic and thermal denaturation studies showed some similarities between beta and pi, but phi A1DH behaved quite differently. It was concluded that pregnancy caused an increase in one of the A1DHs already present in control mice, while phenobarbital treatment resulted in induction of a unique cytosolic A1DH.

Aldehyde Dehydrogenase↗
PubMed1981

Inhibition of rat liver aldehyde dehydrogenase by carbon tetrachloride.

Current data suggests that aldehydic products of lipid peroxidation possess substantial cytotoxic properties. Carbon tetrachloride (CCl4), a potent stimulator of hepatic lipid peroxidation, was tested for possible effects on hepatocellular aldehyde metabolism. CCl4 (1 ml/kg) produced an elevation in serum alanine aminotransferase activity, hepatic fatty infiltration, centrilobular necrosis and significant decreases in the content of hepatic microsomal cytochrome P-450. Concurrently, the aldehyde dehydrogenase (E.C. 1.2.1.3) activity of mitochondrial and cytosolic fractions was significantly depressed. The lower Km aldehyde dehydrogenase located in the mitochondria showed the largest degree of inhibition (46%). An in vitro system which contained the low Km mitochondrial aldehyde dehydrogenase was employed to determine the role of microsomal lipid peroxidation in the inhibition of the enzyme. Aldehyde dehydrogenase was shown to be extremely sensitive to inhibition under conditions of NADPH or NADPH and CCl4-stimulated lipid peroxidation. Reduced glutathione (6 mM) provided complete protection of aldehyde dehydrogenase activity under conditions of NADPH-stimulated lipid peroxidation but could not protect activity loss during CCl4-stimulated microsomal lipid peroxidation. The degree of enzyme activity loss related well with the amount of thiobarbituric reacting substances present in the incubation mixture. These findings show that CCl4 decreases the activity of the aldehyde oxidizing enzyme, aldehyde dehydrogenase. This effect may accentuate cytotoxic effects of reactive aldehydic products generated during lipid peroxidation.

Aldehyde Dehydrogenase↗
PubMed1980

Genetically mediated responses of microsomal ethanol oxidation in mice.

Long-sleep (LS) and Short-sleep (SS) male mice were treated chronically with alcohol for 30 days. Ethanol treated mice were withdrawn from alcohol diet at 8, 12, 16, 20, 24 and 30 days of treatment for the assessment of metabolic tolerance and numerous parameters associated with the microsomal cytochrome P-450 complex. Up to 20 days of ethanol treatment, LS and SS mice displayed nearly the same enhancement of in vivo ethanol elimination rates. AT 24 and 30 days of ethanol treatment, LS mice were found to have significantly greater ethanol elimination rates than SS mice chronically treated with alcohol. The induction of microsomal cytochrome P-450 content and microsomal ethanol oxidation paralleled the acquisition of metabolic tolerance with LS mice displaying significantly greater values of both microsomal parameters at 24 and 30 days of treatment. Aniline hydroxylase was maximally induced (2.5 fold) in both LS and SS mice by 16 days of treatment. Chronic ethanol treatment resulted in a significant induction of ethylmorphine and benzphetamine N-demethylase activity in both LS and SS mice with the SS selected line showing a greater (P < .05) maximal induction. These data are suggestive that the induction of MEOS may have some significance in the acquisition of metabolic tolerance to ethanol and that there may be a genetic predisposition for these adaptive responses.

Alcohol Drinking↗
PubMed1980

The role of liver cytosolic aldehyde dehydrogenase in ethanol metabolism in DBA and C57Bl mice.

Cytosolic aldehyde dehydrogenase (AlDH) activity was increased in DBA and C57Bl mice following phenobarbital (Pb) treatment. The kinetic constants for the control and induced enzymes were similar in both inbred strains. The DBA mice showed enhanced rates of ethanol and acetaldehyde metabolism after Pb treatment, whereas the C57Bl mice did not. It was concluded that the cytosolic enzyme is more important for acetaldehyde metabolism in the DBA than in the C57Bl mice.

Acetaldehyde↗
PubMed1977

Effects of three monoamine oxidase inhibitors on ethanol preference in mice.

These experiments investigated the effects of pargyline, N-[2-(o-Chlorophenoxy)-ethyl]-cyclopropylamine (Lilly 51641), and nialamide on voluntary ethanol consumption of C57BL/6J mice. Both pargyline and Lilly 51641 reduced ethanol preference; in contrast, nialamide did not affect preference, despite the fact that it inhibited MAO activity by more than 90%. A subsequent experiment determined that both pargyline and Lilly 51641 produced substantially greater elevations in acetaldehyde levels than did nialamide. It is suggested that increased acetaldehyde is the mechanism responsible for the reduction in ethanol preference observed with pargyline and Lilly 51641.

Acetaldehyde↗
PubMed1977

Role of liver cytosolic aldehyde dehydrogenase isozymes in control of blood acetaldehyde concentrations.

The role of various cytosolic aldehyde dehydrogenase (ALDH) isozymes in acetaldehyde metabolism was determined. Rats of known genotype (RR, reactor; rr, nonreactor) with respect to induction of a cytosolic enzyme by phenobarbital were used. Animals were treated with either phenobarbital (1.0 mg/ml in drinking water for 3 days) or 75 microng/kg (i.p.) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prior to ethanol treatment (2.5 g/kg). TCDD treatment is known to induce a second cytosolic ALDH isozyme in both RR and rr animals. Phenobarbital increased cytosolic ALDH activity 23-fold only in the RR animals, while TCDD increased activity 155-fold in both groups. Phenobarbital-treated RR rats maintained significantly lower blood acetaldehyde levels at 30, 90 and 150 minutes after ethanol injection compared to control RR animals. Blood acetaldehyde levels in phenobarbital-treated rr rats were not significantly different from rr controls. Administration of TCDD to RR or rr rats did not significantly alter blood acetaldehyde levels at 30, 90 or 150 minutes after ethanol treatment compared to appropriate controls. Similarly, phenobarbital significantly increased blood ethanol elimination rate (1.5 times greater than control) only in RR rats. Ethanol elimination rate was not significantly altered by TCDD in either group. Pargyline (100 mg/kg i.p.) did not significantly inhibit cytosolic ALDH activity, while total mitochondrial ALDH activity was inhibited by 28 and 57% in RR animals receiving TCDD and phenobarbital, respectively. Pargyline significantly increased blood acetaldehyde levels after ethanol administration. However, pretreatment with phenobarbital or TCDD significantly decreased elevated blood acetaldehyde levels resulting from pargyline treatment, with the greatest reduction in the phenobarbital-treated RR animals.

Acetaldehyde↗
PubMedDate not supplied

Ethanol and acetaldehyde metabolism in the pregnant mouse.

Liver aldehyde dehydrogenase (ALDH) activity was found to be two-fold greater in pregnant (days 16-20 of gestation) mice than in non-pregnant controls. A subcellular fractionation revealed that the increase in ALDH activity was confined to the cystosolic fraction of the liver. Kinetic characterization of partially purified liver ALDH revealed similar Km values for either acetaldehyde or propionaldehyde in pregnant and non-pregnant animals. The similarity of apparent Km values suggests that the increase in cytosolic ALDH may involve induction of normally present ALDH isozyme, rather than originating from synthesis of a new enzyme. Induction of liver ALDH was found to significantly decrease blood acetaldehyde concentrations in pregnant mice receiving 2.0 or 3.0 g/kg ethanol when compared to the respective control (non-pregnant) animals. However, differences in blood acetaldehyde levels measured in pregnant and control animals were not apparent when blood ethanol concentrations were below 40 mumol/ml.

Acetaldehyde↗