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D R Petersen

Publications and source records attributed to D R Petersen.

At least 19 recordsLinked to original sources
PubMed1995

The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase.

It has previously been reported that isolated rat hepatocytes rapidly and completely metabolize high concentrations of 4-hydroxy-2,3-(E)-nonenal (4-HNE). However, until this report, the degree to which oxidative-reductive and nonoxidative metabolic pathways function in the depletion of 4-HNE by isolated rat hepatocytes has been speculative. The objective of the present study was to quantitate the extent to which cellular aldehyde dehydrogenases (ALDH; EC 1.2.1.3.), alcohol dehydrogenase (ADH; EC 1.1.1.1.), and glutathione S-transferases (GST; EC 2.5.1.18) function simultaneously during hepatocellular metabolism of 4-HNE. Hepatocytes were incubated with varying concentrations of 4-HNE (50, 100, 250 microM) and reversed-phase HPLC was used to quantitate 4-HNE and the oxidative and reductive metabolites, 4-hydroxy-2-nonenoic acid and 1,4-dihydroxy-2-nonene, respectively. Conjugative metabolism of 4-HNE was determined from the depletion of cellular reduced glutathione (GSH) and concomitant formation of a GSH-4-HNE adduct detected as 2,4-dinitrofluorobenzene derivatives measured by reversed-phase HPLC. Hepatocellular elimination of 4-HNE was estimated at rates of 1.666, 0.902, and 0.219 nmol min-1 10(6) hepatocytes-1 for 50, 100, and 250 microM aldehyde, respectively. At aldehyde concentrations of 50, 100, and 250 microM the maximal concentrations of oxidative (acid) metabolites formed were 5.9, 12.7, and 28.9 nmoles 10(6) hepatocytes-1, whereas the concentrations of the reductive (diol) metabolite were 0.4, 12.6, and 42.3 nmoles 10(6) hepatocytes-1, respectively. The presence of 4-methylpyrazole or cyanamide abolished formation of the reductive metabolite 1,4-dihydroxy-2-nonene or the oxidative metabolite 4-hydroxy-2-nonenoic acid in hepatocyte suspensions. At all 4-HNE concentrations evaluated, hepatocellular glutathione was not completely depleted by the aldehyde and the depletion of cellular reduced GSH corresponded to the production of the GSH-4-HNE conjugate. Metabolism by the alcohol/aldehyde dehydrogenase pathways accounted for approximately 10% of the 4-HNE elimination, while bioconversion by GST represent 50-60% of the total 4-HNE removal by hepatocytes. The enzymatic pathways responsible for the remaining 40% of 4-HNE metabolism remain to be identified. Taken together these results describe the quantitative and dynamic importance of oxidative, reductive, and nonoxidative routes in the metabolism and detoxification of 4-HNE.

Alcohol Dehydrogenase↗
PubMed1995

Iron-induced lipid peroxidation in rat liver is accompanied by preferential induction of glutathione S-transferase 8-8 isozyme.

Since previous studies from this laboratory have suggested that glutathione S-transferase (GST) 8-8 of rat belongs to a distinct subgroup of GST isozymes which may be involved in the detoxification of the products of lipid peroxidation (Zimniak et al., J. Biol. Chem. 269, 992-1000, 1994), during the present studies we examined the effect of iron-induced lipid peroxidation on the expression of GST 8-8 in rat liver. Rats treated with 100 mg/kg body wt iron showed a significant increase in lipid peroxidation in liver. This was accompanied by a concomitant increase in the expression of GST 8-8 in liver as observed in isoelectrophoretic analysis of rat liver GSTs, and an increase in GST activity toward 4-HNE, a toxic product of lipid peroxidation toward which GST 8-8 displays high specific activity. Western blot studies using polyclonal antibodies specifically recognizing GST 8-8 also indicated that, among the GST isozymes of rat liver, GST 8-8 was preferentially induced upon iron treatment. These findings were further confirmed by purifying and quantitating GST 8-8 protein from the controls and iron-treated rats. Significant differences in the specific activities of GST 8-8 purified from the controls and iron-treated rats were observed, indicating that more than one GST isozyme related to GST 8-8 may be present in rat liver. This observation is consistent with the observed heterogeneity in mouse mGSTA4-4 which is an ortholog of rat GST 8-8. Iron treatment also caused significant increase in GSH levels probably because of de novo synthesis as indicated by an increase in gamma-glutamyl cysteine synthetase activity. The results of these studies suggest that GST 8-8, and possibly other related GST isozymes, may play an important role in defense mechanisms against lipid peroxidation.

Aldehydes↗
PubMed1994

Several closely related glutathione S-transferase isozymes catalyzing conjugation of 4-hydroxynonenal are differentially expressed in human tissues.

A human acidic glutathione S-transferase, hGST 5.8, was isolated from heart, pancreas, and brain by a procedure involving immunoadsorption chromatography on immobilized antibodies raised against mouse mGSTA4-4. The human hGST 5.8 enzymes isolated from these tissues had similar pI (5.8) and subunit M(r) (24.5 kDa) values, showed about 17- to 20-fold higher specific activities for 4-hydroxynon-2-enal than that for 1-chloro-2,4-dinitrobenzene, and expressed glutathione peroxidase activity toward phospholipid hydroperoxides. In this respect, the enzymes belong together with rat GST 8-8 and mouse mGSTA4-4 to a subgroup of GSTs involved in the detoxification of lipid peroxidation products. Partial sequencing of CNBr-peptide fragments of hGST 5.8 proteins isolated from various human tissues revealed significant similarity to mGSTA4-4 and the existence of several distinct isoforms differing in their primary structures. These isoforms had similar but nevertheless clearly distinguishable catalytic properties. These results indicate the existence of multiple hGST 5.8-related genes in the humans, which is consistent with our previous studies showing the presence of several closely related genes for the mouse ortholog mGSTA4-4 (Zimniak et al., J. Biol. Chem., 1994, 269, 992-1000).

Aldehydes↗
PubMed1994

Purification and characterization of two rat liver microsomal carboxylesterases (hydrolase A and B).

The enzymatic hydrolysis of para-nitrophenylacetate by rat liver microsomes is predominantly catalyzed by two esterases: one with high affinity (Km approximately 25 microM) and one with low affinity (Km approximately 400 microM) for the substrate. Two kinetically distinct esterases were similarly detected in liver microsomes from mouse, hamster, guinea pig, rabbit, cat, cynomolgus monkey, and human, but only the high-affinity enzyme was detectable in dog liver microsomes. The tissue distribution of these kinetically distinct esterases was examined in rats. High-affinity (Km 20-35 microM esterase activity toward para-nitrophenylacetate was detected in testis, lung, prostate, and pancreas. The activity in testicular microsomes was comparable to that in liver microsomes. Low-affinity (Km 200-700 microM) esterase activity was detected in kidney, small intestine, lung, spleen, heart, and brain. The activity in kidney microsomes was comparable to that in liver microsomes. The high-affinity esterase in testicular and liver microsomes was highly sensitive to the inhibitory effects of phenylmethylsulfonyl fluoride (PMSF), whereas the low-affinity esterase in kidney and liver microsomes was relatively resistant. These results suggested that rat liver microsomes contain two esterases with high activity toward para-nitrophenylacetate, a PMSF-sensitive esterase with high substrate affinity, and a PMSF-insensitive esterase with low substrate affinity. In support of the hypothesis, we have purified and characterized two esterases, designated hydrolases A and B, which appear be the only abundant enzymes in rat liver microsome that rapidly hydrolyze para-nitrophenylacetate. Hydrolase A hydrolyzed para-nitrophenylacetate with high affinity (Km approximately 25 microM), and was inhibited by extremely low concentrations of PMSF (IC50 approximately 100 nM). In contrast, hydrolase B hydrolyzed para-nitrophenylacetate with low affinity (Km approximately 400 microM) and was inhibited only by relatively high concentrations of PMSF (IC50 approximately 100 microM Paraoxon, the active metabolite of parathion, and cresylbenzodioxaphosphorin oxide, the active metabolite tri-ortho-tolylphosphate, completely inhibited the hydrolysis of pra-nitrophenylacetate by rat liver microsomes and by hydrolases A and B, whereas the sulfhydryl agent, para-chloromercurobenzoate, was not inhibition. These results suggest that hydrolases A and B are both serine esterases. The N-terminal amino acid sequence of hydrolases A and B were similar but distinct (23 the first 30 amino acid residues were identical), indicating that these two esterases are isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Amidohydrolases↗
PubMed1992

Metabolism of trans,trans-muconaldehyde by aldehyde and alcohol dehydrogenases: identification of a novel metabolite.

The metabolism of trans,trans-muconaldehyde (MA), a highly reactive alpha,beta-unsaturated dialdehyde, was examined in vitro using purified yeast alcohol and aldehyde dehydrogenases (ADH and ALDH, respectively). In the presence of NAD(+)-fortified ALDH, the mono-oxidation product (acid/aldehyde) was the primary metabolite formed with trace amounts of the dioxidation product (trans,trans-muconic acid). In NADH-fortified reactions with ADH, both the mono- and direduction products (hydroxy/aldehyde and dihydroxy, respectively) were readily detected. Oxidation and reduction products of MA were formed in incubates containing both dehydrogenases together with either NAD+ or NADH. Unexpectedly, an additional metabolite was detected, which was a major product in both NAD(+)- and NADH-fortified systems containing ALDH and ADH in combination and whose formation could be inhibited by pyrazole (an ADH inhibitor). ALDH-mediated oxidation of a synthetic standard of the hydroxy/aldehyde derivative of MA resulted in formation of this new metabolite, which was also a major product formed by rat hepatocytes incubated with MA. Using HPLC/photodiode array detection, the new metabolite was found to cochromatograph and have a uv spectrum identical to that of a synthetic standard of the hydroxy/acid derivative of MA. The metabolite was confirmed as the hydroxy/acid derivative of MA after preparative HPLC, TMS derivatization, and GC/MS analysis. The hydroxy/acid metabolite was not formed during ADH-mediated reduction of the mono-oxidation product of MA, suggesting that this metabolite was formed by yeast dehydrogenases via a primary reduction of MA and subsequent oxidation of the hydroxy/aldehyde to the hydroxy/acid. These data show that the hydroxy/acid derivative is a novel metabolite of MA, which arises from the interaction of both oxidative and reductive routes of metabolism.

Alcohol Dehydrogenase↗
PubMed1992

Enzymatic basis for the transesterification of cocaine in the presence of ethanol: evidence for the participation of microsomal carboxylesterases.

The enzyme-mediated transesterification of the 2-carboxymethyl ester of cocaine to a 2-carboxyethyl ester in the presence of ethanol has been characterized in mice by using both in vitro and in vivo systems. Hepatic subcellular fractionation of mouse livers demonstrated that cocaine transesterification activity was detectable only in the microsomal fraction. The in vitro microsomal transesterification of cocaine in the presence of ethanol was inhibited by fluoride and diisopropylfluorophosphate but was insensitive to physostigmine, thereby indicating that the reaction is specifically catalyzed by a carboxylesterase. The transesterification activity of hepatic microsomes showed saturable Michaelis-Menten kinetics in the presence of increasing concentrations of ethanol or cocaine. Cocaine transesterification specific activity in isolated mouse kidney microsomes was approximately 1.5-fold greater than that measured in the liver, suggesting that the kidney could play a significant role in ethyl ester formation. Collectively, these observations demonstrate that the transesterification of cocaine in the presence of ethanol is probably the result of hepatic and possibly renal carboxylesterases localized in the endoplasmic reticulum. The ethyl ester of cocaine was also detected in the livers of mice coadministered ethanol (3.0 g/kg intragastrically) and cocaine (50 mg/kg i.p.). Cocaine and cocaine ethyl ester displayed similar pharmacokinetic profiles, with hepatic half-lives of approximately 6.5 min. Pretreatment of the mice with 100 mg/kg tri-o-tolylphosphate completely blocked in vivo formation of the ethyl ester metabolite, further supporting the involvement of B-esterases in the transesterification of cocaine to cocaine ethyl ester.

Animals↗
PubMed1991

Lipid aldehyde oxidation as a physiological role for class 3 aldehyde dehydrogenases.

A large number of different unsaturated, saturated and hydroxylated aliphatic aldehydes can be generated during the peroxidation of cellular lipids. This study examined the kinetic properties of purified Class 3 rat aldehyde dehydrogenase (ALDH) with respect to the oxidation of various lipid aldehyde substrates. It also compared the substrate preference of the prototypic Class 3 ALDH with that of the constitutive rat microsomal aldehyde dehydrogenase. The results suggest that (1) microsomal ALDH is a member of the Class 3 aldehyde dehydrogenase family, and (2) the physiological role of the Class 3 ALDHs, including the microsomal form, is the oxidation of medium (6 to 9 carbon) chain length saturated and unsaturated aldehydes generated by the peroxidation of cellular lipids. Short chain aliphatic aldehydes, such as a malondialdehyde and 4-hydroxyalkenals, are not substrates for the Class 3 aldehyde dehydrogenases.

Aldehyde Dehydrogenase↗
PubMed1991

Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase-mediated acetaldehyde oxidation by trans-4-hydroxy-2-nonenal.

The hepatic oxidation of ethanol has been demonstrated to cause peroxidation of cellular membranes, resulting in the production of aldehydes that are substrates for hepatic aldehyde dehydrogenases. It was the purpose of this study to evaluate the cooxidation of the lipid peroxidation product, trans-4-hydroxy-2-nonenal, and acetaldehyde by high-affinity mitochondrial aldehyde dehydrogenase, which is of prominent importance in the oxidation of ethanol-derived acetaldehyde. Experiments were performed for determination of kinetic parameters for uninhibited acetaldehyde and 4-hydroxynonenal oxidation by semi-purified mitochondrial aldehyde dehydrogenase prepared from male Sprague-Dawley rat liver. The affinity of the enzyme for the substrate at low substrate concentrations and the Michaelis-Menten constant of mitochondrial aldehyde dehydrogenase for acetaldehyde were 25 and 10 times greater, respectively, than those determined for 4-hydroxynonenal. Coincubation of acetaldehyde with physiologically relevant concentrations of 4-hydroxynonenal (0.25 to 5.0 mumol/L) with mitochondrial aldehyde dehydrogenase demonstrated that 4-hydroxynonenal is a potent competitive or mixed-type inhibitor of acetaldehyde oxidation, with concentration of 4-hydroxynonenal required for a twofold increase in the slope of the Lineweaver-Burk plot for acetaldehyde oxidation by ALDH of 0.48 mumol/L. The results of this study suggest that the aldehydic lipid peroxidation product, trans-4-hydroxy-2-nonenal, is a potent inhibitor of hepatic acetaldehyde oxidation and may potentiate the hepatocellular toxicity of acetaldehyde proposed to be an etiological factor of alcoholic liver disease.

Acetaldehyde↗
PubMed1991

Hepatic biochemical changes as a result of acute cocaine administration in the mouse.

The biochemical mechanism of cocaine hepatotoxicity is thought to involve enzymatic formation of reactive metabolites. The exact hepatocellular effects of these metabolites have yet to be established. This study was designed to monitor, in a time course after an acute cocaine dose, biochemical parameters that are important in cellular defense and homeostasis in vivo. The hepatic parameters measured were ATP as an indicator of cellular energetic status, reduced and oxidized glutathione, NADH and NADPH as measures of redox changes, and thiobarbituric acid-reactive products and microsomal conjugated dienes to determine the extent of lipid peroxidation. In addition, serum ALT levels were determined at each time point to assess the extent of toxicity. Inbred mouse strains selected for their relative sensitivity (male DBA/2Ibg) and resistance (male C57BL/6Ibg) to cocaine-mediated hepatotoxicity were used in this study. Animals were given an acute 50 mg/kg intraperitoneal dose of cocaine, and at various times after administration the hepatic and serum determinations were made. The results of this study confirm the strain difference in cocaine-induced hepatotoxicity and also indicate that there are changes in the biochemistry of the liver that are brought about by acute cocaine administration. In particular, depletions of hepatic GSH, NADH, NADPH and ATP coupled with significant increases in oxidized glutathione were observed in the DBA mouse. C57BL mice showed similar decreases in reduced glutathione, NADH and NADPH but exhibited no significant depletion of hepatic ATP. A similar extent of lipid peroxidation was seen in both mouse strains after cocaine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1990

Potentiation of cocaine-mediated hepatotoxicity by acute and chronic ethanol.

Cocaine has been associated with hepatotoxicities in man and is a potent hepatotoxin in mice. The theorized toxic metabolite of cocaine is thought to be generated by a multistep pathway mediated primarily by cytochrome P-450. Ethanol, whether administered acutely or chronically, is known to have diverse effects on numerous hepatocellular biochemical pathways. The present study was designed to characterize not only the effects of acute and chronic ethanol on cocaine-mediated hepatotoxicity but also on the hepatic reduced glutathione (GSH) in an attempt to correlate depletions of GSH with changes in toxicity. Male and female mice were administered an acute 50 mg/kg dose of cocaine either 1 hr after an acute 3 g/kg dose of ethanol, or after 5 days of consuming an ethanol-containing liquid diet. Serum alanine aminotransferase (ALT) activity was measured in blood collected 24 hr after the acute cocaine dose. In addition, hepatic reduced glutathione (GSH) and cytochrome P-450 content were measured at the point in the pretreatment where cocaine was administered. The results of this study indicate that both acute and chronic ethanol pretreatment can markedly enhance the hepatotoxicity of cocaine in both male and female mice and that the enhancement is significantly greater after chronic ethanol pretreatment. Hepatic GSH was slightly decreased 1 hr after an acute dose of ethanol and significantly decreased after chronic ethanol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1989

Oxidation of aldehydic products of lipid peroxidation by rat liver microsomal aldehyde dehydrogenase.

Lipid peroxidation in microsomal membranes produces a large number of aldehydes, alcohols, and ketones, some of which have been shown to be cytotoxic. This study has determined the kinetic parameters for the oxidation of aldehyde lipid peroxidation products by purified rat hepatic microsomal aldehyde dehydrogenase (ALDH). Livers were obtained from male Sprague-Dawley rats for preparation of microsomal ALDH which was purified 400-fold. Kinetic parameters, Vmax and V/K, were determined for saturated and unsaturated aldehydes of three to nine carbons in length in the presence of NAD+. Of the aldehydes examined, only acrolein and 4-hydroxynonenal were not oxidized by ALDH. The Vmax values (mumol NADH produced/min/mg protein) increased linearly with carbon chain length and ranged from 6.5 to 23 for the saturated series and 4.0 to 9.0 for the unsaturated aldehydes. The affinity constant V/K (nmol NADH produced/min/mg protein/nmol aldehyde/liter) also increased with carbon chain length and ranged from 12 to 9000 for the saturated aldehydes and 13 to 5300 for the unsaturated aldehydes. These results suggest that microsomal ALDH may serve a biological role for detoxification of reactive aldehydes produced by lipid peroxidation of microsomal membranes.

Alcohol Dehydrogenase↗
PubMed1989

LS X SS recombinant inbred strains of mice: initial characterization.

In order to assess the genetic correlates of differences in ethanol-induced anesthesia, a set of 27 recombinant inbred (RI) strains was derived from an initial cross of the "long-sleep" (LS) and "short-sleep" (SS) selected lines of mice. In generations F24 and F25, samples of 534 and 580 mice from the LSXSS RI strains were tested for fall time, sleep time, and blood ethanol at awakening subsequent to intraperitoneal injection of a 4.1-g/kg body weight dose of ethanol. Approximately 2 weeks later, mice from F24 were also tested for body temperature lowering and blood-ethanol elimination rate (beta 60). Differences among the average ethanol-induced sleep-time scores of the RI strains are large (ranging from 36 to 171 min) and account for over 50% of the observed variance. Effects due to generation, sex, litters within strains, and the interaction between strain and generation are also significant, but account for relatively small proportions of the total variance. Quantitative genetic analyses of these data suggest that differences in sleep-time scores are polygenic; however, allelic differences at the albino (c) locus may have a pleiotropic effect. Genetic correlations between sleep time and blood ethanol at awakening (-0.79) and between body temperature 60 min after injection and beta 60 (+0.48) are significant. Because differences among the LSXSS RI strains are large and highly reliable, they should be valuable animal models for testing more searching hypotheses about the etiology of individual differences in ethanol-induced anesthesia.

Animals↗
PubMed1989

Metabolism of the glutathione-acrolein adduct, S-(2-aldehydo-ethyl)glutathione, by rat liver alcohol and aldehyde dehydrogenase.

The oxidative and reductive metabolism of the acrolein-glutathione adduct, S-(2,aldehydo-ethyl)glutathione, by rat liver aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) was characterized. The glutathione-acrolein adduct is oxidized to the respective acid by two different forms of ALDH contained in rat liver cytosol which are distinct from two forms of ALDH present in the mitochondria also capable of oxidizing the aldehyde moiety of the adduct. Extensive kinetic characterization (Km, Vmax and V/K parameters) of the ALDH enzymes suggest that the glutathione-acrolein adduct is oxidized most efficiently by one form of mitochondrial ALDH which is 3.5 to 175 times more active (based on V/K comparisons) than the other forms of mitochondrial and cytosolic ALDH evaluated. The glutathione-acrolein adduct is also subject to reductive metabolism by rat liver ALH. However, the Km value (877 microM) for reduction of the adduct suggests that this would be a minor pathway of metabolism. Collectively, these results indicate that the glutathione-acrolein adduct formed after exposure to acrolein, or as a result of allyl alcohol oxidation and cyclophosphamide metabolism, can be oxidized by hepatic ALDH or ADH, respectively. However, the kinetic parameters for these pathways suggest that micromolar concentrations of this adduct may accumulate before these enzyme systems mediate significant oxidative or reductive pathways of detoxification. The proposition that the glutathione-acrolein adduct may play a role in acrolein-mediated hepatotoxicity is discussed.

Alcohol Dehydrogenase↗
PubMed1988

Sex and strain differences in the hepatotoxic response to acute cocaine administration in the mouse.

Cocaine-induced hepatotoxicity was examined in vivo in a dose-responsive manner in C57BL/6Ibg, DBA/2Ibg, C3H/2Ibg, and Balb/cJ mice. Serum glutamic-pyruvic transaminase (SGPT) activities were determined 24 hours after intraperitoneal (IP) administration of cocaine (20 to 100 mg/kg). Significant elevations (100- to 150-fold) in SGPT were observed in male mice receiving cocaine. Significant differences in sensitivity to cocaine-induced hepatotoxicity were found among males of the inbred strains, with Balb being most sensitive and C57BL being least sensitive and C3H and DBA strains exhibiting intermediate sensitivity. Female mice of the four inbred strains were more resistant than males to cocaine-mediated hepatotoxicity, as indicated by only twofold to tenfold elevations in SGPT values. Among the females, sensitivity of the four inbred strains--as indicated by dose response curves--fell into two categories: the sensitive strains (C3H and C57BL) and the resistant strains (Balb and DBA). Pretreatment of males of the four inbred strains with the P-450 inducer phenobarbital resulted in enhancement of cocaine-mediated hepatotoxicity in the C57BL and Balb but not the C3H and DBA mice. Phenobarbital pretreatment of females of the four inbred strains resulted in enhancement of the hepatotoxic response to cocaine in the C3H, DBA, and Balb mice. Phenobarbital-pretreated C57BL females exhibited a 100% mortality rate after the acute cocaine dose, and thus no determination of hepatotoxicity could be established for them. These data demonstrate sex and strain differences in cocaine-induced hepatotoxicity and suggest that phenobarbital pretreatment does not uniformly enhance the hepatotoxicity of cocaine.

Alanine Transaminase↗
PubMed1988

Cocaine-induced biochemical changes and cytotoxicity in hepatocytes isolated from both mice and rats.

The mechanism of cocaine-induced cytotoxicity was investigated in hepatocytes isolated from both male C3H mice and male Sprague-Dawley rats. Cocaine was more cytotoxic to mouse hepatocytes than rat and induced reduced glutathione (GSH) depletion prior to marked increases in cytotoxicity in both systems. In both mouse and rat cells, GSH depletion was accompanied by GSSG production, but in rat cells, quantitative measures suggested that other mechanisms contributed to GSH depletion. No cocaine-induced depletion of protein-thiol groups or generation of protein-glutathione mixed disulfides could be detected in rat cells. Cocaine induced lipid peroxidation, using malondialdehyde (MDA) production as an index of the peroxidation process, in both mouse and rat hepatocytes. Inhibition of MDA production to below control levels using the antioxidant N,N'-diphenyl-phenylene diamine (DPPD) however, had no inhibitory effect on cocaine-induced cytotoxicity in either mouse or rat cells. These data suggest that neither generalized protein thiol depletion nor lipid peroxidation are critical determinants of cocaine-induced cytotoxicity in cellular systems.

Animals↗