Search PubMed⌕ Search

Biomedical subjects

S D Nelson

Publications and source records attributed to S D Nelson.

At least 55 records · Page 3Linked to original sources
PubMed1997

Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long-term isoniazid.

OBJECTIVE: To determine in patients receiving isoniazid prophylaxis whether an increase in the CYP2E1 dependent formation clearance of acetaminophen (paracetamol) to N-acetyl-p-benzoquinone imine (NAPQI) occurs during a normal 24-hour isoniazid dose interval and whether the interaction is dependent on acetylation status. METHODS: Acetaminophen elimination kinetics were determined on four different occasions. Ten subjects were assigned to receive acetaminophen either simultaneously with the 8 am dose of isoniazid or 12 hours after the isoniazid dose. One week later, on the last day of isoniazid therapy, subjects received acetaminophen at the alternate time of day. The control phase acetaminophen administrations were repeated 1 and 2 weeks later, following the initial randomization. Isoniazid acetylation (NAT2) genotype was determined by analysis of genomic DNA obtained from peripheral blood leukocytes. RESULTS: The mean NAPQI formation clearance was inhibited 57% when acetaminophen and isoniazid were coadministered but was unchanged compared with time-matched control when acetaminophen was given 12 hours after the isoniazid dose. However, when data from subjects was segregated according to isoniazid (INH) acetylation phenotype, the mean ratio of NAPQI formation clearances (+INH/-INH) with 8 PM acetaminophen was significantly higher for fast acetylators compared with slow acetylators (1.36 versus 0.68; p = 0.006). CONCLUSIONS: Fast metabolizers of isoniazid appeared to clear the inducer or inhibitor from the active site of CYP2E1 more rapidly, which resulted in an increased formation of NAPQI 12 hours after the isoniazid dose. In contrast, formation of NAPQI for slow isoniazid metabolizers remained inhibited.

Acetaminophen↗
PubMed1997

Inactivation of glyceraldehyde-3-phosphate dehydrogenase by a reactive metabolite of acetaminophen and mass spectral characterization of an arylated active site peptide.

Acetaminophen (4'-hydroxyacetanilide, APAP) is a widely used analgesic and antipyretic drug that can cause hepatic necrosis under some circumstances via cytochrome P450-mediated oxidation to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Although the mechanism of hepatocellular injury caused by APAP is not fully understood, it is known that NAPQI forms covalent adducts with several hepatocellular proteins. Reported here is the identification of one of these proteins as glyceraldehyde-3-phosphate dehydrogenase [GAPDH, D-glyceraldehyde-3-phosphate: NAD+ oxidoreductase (phosphorylating), EC 1.2.1.12]. Two hours after the administration of hepatotoxic doses of [14C]APAP to mice, at a time prior to overt cell damage, hepatocellular GAPDH activity was significantly decreased concurrent with the formation of a 14C-labeled GAPDH adduct. A nonhepatotoxic regioisomer of APAP, 3'-hydroxyacetanilide (AMAP), was found to decrease GAPDH activity to a lesser extent than APAP, and radiolabel from [14C]AMAP bound to a lesser extent to GAPDH at a time when its overall binding to hepatocellular proteins was almost equivalent to that of APAP. In order to determine the nature of the covalent adduct between GAPDH and APAP, its major reactive and toxic metabolite, NAPQI, was incubated with purified porcine muscle GAPDH. Microsequencing analysis and fast atom bombardment mass spectrometry (FAB-MS) with collision-induced dissociation (CID) were used to characterize one of the adducts as APAP bound to the cysteinyl sulfhydryl group of Cys-149 in the active site peptide of GAPDH.

Acetaminophen↗
PubMed1997

Characterization of carbamazepine metabolism in a mouse model of carbamazepine teratogenicity.

The disposition of carbamazepine (CBZ) was investigated in the SWV mouse. A 14C-CBZ dose was administered to CBZ pretreated mice, and the distribution of radiolabeled material was determined. Twenty-four hours after the 14C-CBZ dose, 92.5% of the dose was accounted for in urine (56%), in the visera and carcass (22%), in feces (11%), and expired as 14CO2 (2%). CBZ metabolites present in hydrolyzed urine were also identified using a combination of spectroscopic techniques. CBZ, CBZ-10,11-epoxide (CBZE), 2- and 3-hydroxy-CBZ, methylsulfonyl-CBZ, and glucuronides of CBZ and CBZE accounted for 64% of total urinary radioactivity (0-24 hr) in CBZ pretreated mice. Minor metabolites of CBZ included novel cysteine and N-acetylcysteine conjugates of CBZ, as well as a methylsulfonyl conjugate of CBZE not previously reported. The urinary excretion of these thioether conjugates was increased in CBZ/phenobarbital pretreated mice and decreased in CBZ/stiripentol pretreated mice in comparison with CBZ-only treated mice. Preliminary studies of the effects of phenobarbital and stiripentol on the urinary abundance of these metabolites are consistent with the modulation of teratogenicity in the SWV mouse by the same pretreatments. These data suggest the formation of thioether metabolites of CBZ may be related to CBZ teratogenicity in the SWV mouse.

Animals↗
PubMed1997

Mechanism of cytochrome P450 activation by caffeine and 7,8-benzoflavone in rat liver microsomes.

Caffeine and 7,8-benzoflavone activate CYP3A2 in rat liver microsomes. Both activators appear to enhance enzyme activity by an increase in Vmax and to a lesser extent a decrease in Km. Additive effect studies demonstrated that the two activators oppose one another's effect. Electron transfer steps in the cytochrome P450 cycle are involved in the mechanism of cytochrome P450 activation, as indicated by the lack of effect of caffeine or 7,8-benzoflavone on cumene hydroperoxide-supported oxidation of acetaminophen by cytochrome P450. The involvement of cytochrome b5 in the formation of N-acetyl-p-benzoquinone imine (NAPQI) was implicated through a synergistic effect of NADH on the NADPH-supported reaction. Anti-cytochrome b5, but not anti-cytochrome P450 reductase IgG, diminished the activation effect of caffeine on NAPQI formation. Neither antibody altered the effect of 7,8-benzoflavone on NAPQI formation. The impairment of NAPQI formation by cytochrome b5 antibody suggests that cytochrome P450 activation by caffeine but not 7,8-benzoflavone is mediated in part through enhancement of the transfer of the second electron to cytochrome P450 from cytochrome b5.

Animals↗
PubMed1997

Wavelet analysis of SAECG to identify patients with conduction defects at risk for sudden cardiac death.

The aim of this study was to determine how Wavelet transform analysis of signal-averaged ECGs can identify patients with conduction defects who are at high risk for development of ventricular tachycardia. In this study, 34 SA-ECGs and programmed electrical stimulation (PES) reports were obtained from the OSU Department of Cardiology Database (1988-1996) and divided into two groups: 17 patients that had inducible monomorphic VT by PES (VT+) and 17 that showed no arrhythmias (VT-). We used Morlet's wavelet to analyze the X, Y, Z, and RMS vector magnitudes in each group. The mean duration from the peak of the RMS vector magnitude to the QRS offset was statistically different with a T value (2-tailed distribution, unequal variance) of 0.033. We noted statistically significant (p < 0.0001) differences in Wavelet energies for 44 msec after the peak of the RMS vector magnitude largest in the Z lead, the first 22 msec, and frequency bins less than 131 Hz. Although no clinical marker could be determined using Wavelet analysis to distinguish the the VT+ from the VT- group, the results from this study show that their SA-ECGs are indeed different even though the optimal analysis has not yet been devised.

Cardiac Pacing, Artificial↗
PubMed1996

Baculovirus expression and purification of human and rat cytochrome P450 2E1.

High-level expression of human and rat cytochrome P450 2E1 (CYP2E1) was achieved using a baculovirus expression system. A full length cDNA encoding human CYP2E1 was cloned from a human liver cDNA library and sequenced using the dideoxy sequencing method. Insect cells were infected with the homologous recombinant baculoviruses containing the human and rat CYP2E1 cDNAs, respectively. The infected cells were harvested at a time when 450-nm peak intensities were at a maximal level and there was no 420-nm peak observed in the reduced CO difference spectrum. Both human and rat CYP2E1 were then purified to electrophoretic homogeneity by a relatively rapid and efficient procedure. The specific contents of the purified human and rat CYP2E1 were 13.8 and 17.0 nmol/mg protein, respectively. The lambda(max) of the reduced CO difference spectra of both purified rat and human CYP2E1 was found to be 451.5 nm. When the purified rat and human CYP2E1 were reconstituted with purified rat NADPH-P450 reductase and human cytochrome b5, they were able to metabolize several known CYP2E1 substrates: chlorzoxazone, p-nitrophenol, acetaminophen, and carbon tetrachloride. Interestingly, cytochrome b5 markedly stimulated the CYP2E1-mediated two-electron oxidation of the first three substrates, while it had almost no effect on the presumed one-electron reduction of carbon tetrachloride.

Animals↗
PubMed1996

Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature.

BACKGROUND: Pennyroyal is a widely available herb that has long been used as an abortifacient despite its potentially lethal hepatotoxic effects. However, quantitative data for pennyroyal constituents and their metabolites in humans have not been previously reported. OBJECTIVES: To quantify pennyroyal metabolites in human overdose, to correlate these findings with clinical variables, and to place these findings in the context of previously reported cases of pennyroyal toxicity. DESIGN: Clinical case series of pennyroyal ingestions; quantification of pennyroyal metabolites by gas chromatography and mass spectrometry; qualitative detection of protein-bound adducts of the metabolites of pennyroyal constituents in human liver by Western blot assay; and review of the literature based on a search of MEDLINE, Index Medicus, and the reference citations of all available publications. RESULTS: We report four cases of pennyroyal ingestion. One patient died, one received N-acetylcysteine, and two ingested minimally toxic amounts of pennyroyal and were not treated with N-acetylcysteine. In the fatal case, postmortem examination of a serum sample, which had been obtained 72 hours after the acute ingestion, identified 18 ng of pulegone per mL and 1 ng of menthofuran per mL. In a serum sample from the patient treated with N-acetylcysteine, which had been obtained 10 hours after ingestion, the menthofuran level was 40 ng/mL. Review of 18 previous case reports of pennyroyal ingestion documented moderate to severe toxicity in patients who had been exposed to at least 10 mL of pennyroyal oil. CONCLUSION: Pennyroyal continues to be an herbal toxin of public health importance. Data on human metabolites may provide new insights into the toxic mechanisms and treatment of pennyroyal poisoning, including the potential role of N-acetylcysteine. Better understanding of the toxicity of pennyroyal may also lead to stricter control of and more restricted access to the herb.

Acetylcysteine↗
PubMed1996

Primary immunolocalization of estrogen and progesterone target cells in the human anterior cruciate ligament.

To identify estrogen and progesterone target cells in the human anterior cruciate ligament immunohistochemical localization of both estrogen and progesterone receptors was performed in 17 specimens of human anterior cruciate ligament. All ligament specimens were obtained at surgery. Thirteen specimens were from women, and four were from men: the average age was 57 years (range, 18-78 years). Eleven specimens (from nine women and two men) came from total knee replacements for osteoarthritis of the knee: three (from two women and one man), from reconstructions of the anterior cruciate ligament: two (both from women), from medial meniscectomies; and one (from a man), from an amputation secondary to chondrosarcoma of the pelvis. An immunoperoxidase method using monoclonal antibodies to the estrogen and progesterone receptors was employed to identify estrogen and progesterone target cells in the anterior cruciate ligament. Staining of both receptors was demonstrable in 14 specimens and in the remaining three specimens less than 15% of the cells were stained. Both estrogen and progesterone receptors were localized to synoviocytes in the synovial lining, fibroblasts in the anterior cruciate ligament stroma and cells in the blood vessel walls of the ligament. This demonstration of receptors for estrogen and progesterone in the cells of anterior cruciate ligament suggests that female sex hormones may have an effect on its structure and composition.

Adolescent↗
PubMed1996

The influence of sodium channel blockade on the defibrillation energy requirements of biphasic versus monophasic shocks.

The sodium channel-blocking actions of some Class I antiarrhythmic agents can increase the defibrillation energy requirements (DER) of monophasic shock waveforms. The influence of sodium channel blockade on biphasic shocks is less certain. The purpose of this study was to compare, in a randomized, placebo controlled study, the influence of lidocaine on the DER of biphasic and monophasic shock waveforms in a canine model of transvenous internal defibrillation. The DER was determined by the iterative increment-decrement protocol. Monophasic and biphasic shock DERs were tested at baseline and during lidocaine infusion (group A) or saline control (group B). Group A biphasic shock DERs increased significantly from a baseline of 12.1 +/- 3.6 J to 19.1 +/- 9.3 J when compared to group B (P = 0.005). In group A, the mean DER during lidocaine was significantly higher with monophasic shocks than biphasic shocks (29.6 +/- 11.8 J vs 19.1 +/- 9.3 J, respectively; P < 0.003), but the magnitude of change in biphasic versus monophasic shock DERs was not significantly different (F = 1.78; p = 0.193). There was a linear relationship between the baseline DER and the DER during lidocaine (r2 = 0.63, P < 0.0001). Sodium channel blockade with lidocaine increases the DER of both monophasic and biphasic shocks. However, the DER of biphasic shocks during lidocaine are significantly lower than monophasic shock DERs, a finding that can be explained by the linear relationship between the baseline DER and the DER during lidocaine. These results may have favorable implications for the use of Class I antiarrhythmics with biphasic shock defibrillators.

Animals↗
PubMed1996

Effects of caffeine and theophylline on acetaminophen pharmacokinetics: P450 inhibition and activation.

Metabolism of acetaminophen (APAP) to its reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is mediated by cytochrome P450. A pharmacokinetic study was conducted to quantitate changes in the formation clearance (Cl(f)) of NAPQI to assess in vivo the activation and inhibition of NAPQI formation by methylxanthines. Cl(f) of NAPQI was unaltered by methylxanthine administration in saline-pretreated rats. In phenobarbital-induced rats receiving a nontoxic dose of APAP (100 mg/kg i.v.), a single dose of caffeine (100 mg/kg i.p.) co-administered with APAP increased the Cl(f) of NAPQI formation from 0.58 +/- 0.47 to 2.08 +/- 1.1 1 ml/min/kg (P = .01). Unlike caffeine, theophylline (93 mg/kg i.p.) had no effect on the Cl(f) of NAPQI in phenobarbital-induced rats. The increase in the Cl(f) of NAPQI immediately after a single dose of caffeine demonstrates that P450 activation by caffeine can occur in vivo, as we observed previously in microsomes. The same dose of APAP and methylxanthines also was administered to rats induced with methylcholanthrene. The co-administration of either a single dose of caffeine or theophylline diminished the Cl(f) of NAPQI by 86% (P = .01) and 52% (P = .03), respectively. These in vivo results agree with our previous studies of the effects of the methylxanthines on the formation of NAPQI in rat liver microsomes.

Acetaminophen↗
PubMed1996

Protein-reactive metabolites of carbamazepine in mouse liver microsomes.

The character of reactive metabolites formed from carbamazepine (CBZ) was sought in incubations of [14C]CBZ in hepatic microsomes prepared from adult female mice of a strain (SWV/Fnn) susceptible to CBZ-induced teratogenicity. The formation of radio-labeled protein adducts was used as an index of reactive metabolite exposure. A dependence on cytochrome P450 was shown by a requirement for NADPH and inhibition by carbon monoxide, 1-aminobenzotriazole, piperonyl butoxide, and stiripentol. The addition of ascorbic acid, caffeic acid, N-acetylcysteine, and glutathione decreased the rate of binding of the radiolabel from [14C]CBZ to microsomal protein by more than 50%. The addition of glutathione transferases diminished protein adduct formation beyond that seen with glutathione alone. Evidence for the formation of an arene oxide was sought through the use of inhibitors of epoxide hydrolases, including cyclohexene oxide, chalcone oxides (with the addition of cytosol as appropriate), and by the addition of recombinant human soluble and microsomal epoxide hydrolases and recombinant rat microsomal epoxide hydrolase. The microsomal epoxide hydrolases decreased the velocity of 14C-labeled protein adduct formation by approximately 23%, whereas inhibitors had no effect, most likely because of the low native activity of microsomal epoxide hydrolase in mice. Both DT-diaphorase and catechol-O-methyltransferase diminished 14C-labeled protein adduct formation by 54% and 45%, respectively. The data suggest that the major reactive metabolites formed from CBZ by adult female SWV/Fnn liver microsomes are quinones and arene oxides.

Animals↗
PubMed1996

Teratogenicity of carbamazepine-10, 11-epoxide and oxcarbazepine in the SWV mouse.

The mechanism of carbamazepine (CBZ)-related teratogenicity was investigated in the SWV mouse by contrasting the effects of CBZ-10, 11-epoxide (CBZE) and oxcarbazepine (OXC) treatments. Dietary CBZE administration was initiated 2 weeks before mating and continued through day 18 of gestation. OXC was administered to pregnant dams by gavage on day 6 of gestation and continued through day 18 of gestation. Maternal plasma concentrations of CBZE ranged from 1.4 to 17.7 micrograms/ml and OXC ranged from 6.1 to 15.9 micrograms/ml. In comparison, clinical plasma concentrations of CBZE ranged from 1 to 2 micrograms/ml and OXC plasma concentrations were 1 microgram/ml or less. The incidence of malformation were 14%, 27% and 26% after daily CBZE doses of 300, 600 and 1000 mg/kg, respectively, compared with a 6% incidence in no-drug control mice, P < .05. The incidence of malformation was 8% after exposure at the highest tolerable dose of OXC (1100 mg/kg/day), compared with a 5% incidence in no-drug controls, P > .05. Phenobarbital cotreatment (45 mg/kg/day) with OXC (1100 mg/kg/day) did not lead to changes in the incidence of malformation when compared with OXC (1100 mg/kg/day) dosed alone. These data are consistent with a teratogenic CBZ metabolite, possibly CBZE, or with oxidation of CBZE or CBZ at positions on the aromatic ring leading to the formation of reactive intermediates such as arene oxides or quinones.

Animals↗
PubMed1995

Metabolism of 1,2-dibromo-3-chloropropane by glutathione S-transferases.

The metabolism of 1,2-dibromo-3-chloropropane (DBCP), measured as the formation of water soluble metabolites and metabolites covalently bound to macromolecules, was studied in isolated rat liver, kidney, and testicular cells, in subcellular fractions, and with purified rat and human glutathione S-transferases (GSTs). The rate of formation of water soluble metabolites in the cells were in the order liver > kidney > testis. The rate of covalent macromolecular binding of reactive DBCP metabolites in the different cell types was of the same relative order. Pretreatment of the cells with the GSH depleting agent diethyl maleate (DEM) markedly decreased the rate of covalent binding in all cell types. Both the overall metabolism and the formation of DBCP metabolites that covalently bound to macromolecules, were substantially higher in rat testicular cells compared to hamster testicular cells. Rat liver cytosol and microsomes, and various purified rat and human GSTs extensively metabolized DBCP to water soluble metabolites in the presence of GSH. When compared to isolated cells, substantially lower rates of binding per mg protein could be observed in subcellular fractions. Binding of DBCP was detected in the microsomal and cytosolic fractions in the absence of NADPH, though in microsomes fortified with a NADPH-regenerating system, the generation of reactive DBCP metabolites was approximately doubled. Studies with purified rat GST isozymes showed that the relative overall GSH conjugation activity with DBCP was in the following order: GST form 3-3 > 2-2 approximately 12-12 > 1-1 > 4-4 approximately 8-8 approximately 7-7. Furthermore, human GST forms also readily metabolized DBCP with activities of GST A1-2 > A2-2 approximately A1-1 > M1a-1a > M3-3 approximately P1-1.

Animals↗
PubMed1995

Comparative toxicity of (+)-(R)- and (-)-(S)-1,2-dibromo-3-chloropropane.

The haloalkane 1,2-dibromo-3-chloropropane (DBCP), an environmental pollutant that was widely used as a soil fumigant, is a carcinogen and a mutagen and displays target-organ toxicity to the testes and the kidneys. Because little is known about effects of stereochemistry on the metabolism and toxicity of halogenated alkyl compounds and because DBCP, which has a chiral center at C-2, may show enantioselectivity in its metabolism and/or toxicities, the optically pure enantiomers of DBCP were tested in vivo in rats for organ toxicity as well as for bacterial mutagenicity. Organ toxicity studies showed that (S)-DBCP was slightly more renal toxic than (R)-DBCP but was not significantly more toxic than the racemate, and that no significant differences were observed in the extents of testicular necrosis and atrophy caused by either enantiomer or the racemate. In contrast, (R)-DBCP was more mutagenic than either (S)-DBCP or the racemate to Salmonella typhimurium (S. typhimurium) strains TA 100 and TA104. However, there was little or no enantioselectivity in glutathione S-transferase (GST)-catalyzed conjugation reactions of glutathione with DBCP based on the lack of selectivity in the rates of disappearance of the enantiomers of DBCP in the presence of glutathione (GSH) and GSTs as monitored by chiral gas chromatography (GC).

Animals↗
PubMed1995

Deuterium isotope effect on the metabolism of the flame retardant tris(2,3-dibromopropyl) phosphate in the isolated perfused rat liver.

The metabolism of tris(2,3-dibromopropyl) phosphate (Tris-BP) was compared with that of completely deuterated Tris-BP (D15-Tris-BP) in an isolated, recirculating rat liver perfusion system in order to determine the relative quantitative importance of two different biotransformation pathways of Tris-BP: (i) cytochrome P450-mediated metabolism and (ii) GSH S-transferase-mediated metabolism. To accomplish this we quantitated the biliary excretion of S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolite for cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl) glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediated metabolism. Complete deuterium substitution of Tris-BP significantly decreased the formation of GSOH, whereas there was no effect on the formation of GSOHOH. Because our previous studies showed a large decrease in genotoxicity of D15-Tris-BP compared to Tris-BP, the present results support our hypothesis that cytochrome P450-mediated metabolism is responsible for the genotoxic effects of Tris-BP in the rat liver.

Animals↗
PubMed1995

Identification of N-acetylcysteine conjugates of 1,2-dibromo-3-chloropropane: evidence for cytochrome P450 and glutathione mediated bioactivation pathways.

The haloalkane 1,2-dibromo-3-chloropropane (DBCP) is a carcinogen, mutagen, nephrotoxin, and testicular toxin. The identification of N-acetylcysteine conjugates of DBCP provides information on GSH mediated and cytochrome P450 mediated bioactivation pathways in the expression of DBCP-induced toxicities. N-Acetylcysteine conjugates excreted in the urine of male Sprague-Dawley rats administered DBCP, C1D2-DBCP, C2D1-DBCP, C3D2-DBCP, or D5-DBCP (80 mg/kg) were purified by reverse-phase HPLC as their methyl ester derivatives and characterized by fast atom bombardment tandem mass spectrometry. These metabolites were also converted to tert-butyldimethylsilyl ether derivatives and analyzed by gas chromatography-mass spectrometry (GC-MS) to facilitate the identification of N-acetyl-S-(2,3-dihydroxypropyl)cysteine (Ia), an apparent regioisomer of Ia, 2-(S-(N-acetylcysteinyl))-1,3-propanediol (Ib), N-acetyl-S-(3-hydroxypropyl)cysteine (IIa), and N-acetyl-S-(3-chloro-2-hydroxypropyl)-cysteine (III). Metabolites Ia, Ib, and III displayed quantitative retention of deuterium, an observation consistent with the formation of episulfonium ion intermediate(s) in their biogenesis. Mercapturate IIa retained three atoms of deuterium from D5-DBCP, and two atoms of deuterium from the dideuterio analogs (C1D2-DBCP and C3D2-DBCP), thus invoking P450 mediated formation of 2-bromoacrolein (2-BA) as an intermediate in the biogenesis of IIa. A mechanism is proposed in which conjugate addition of GSH to 2-BA, subsequent episulfonium ion formation, and addition of GSH afford 1,2-(diglutathion-S-yl)propanal. Glutathione mediated reduction is invoked to afford S-(3-hydroxypropyl)GSH which would be excreted in the urine as IIa. The quantitative retention of deuterium from C1D2-DBCP or C3D2-DBCP was indicative of isotopically sensitive branching of P450 metabolism at either C1 or C3 to afford 2-BA. C2D1-DBCP showed a 30% retention of 1 deuterium atom in IIa; the loss of the deuterium is consistent with 2-BA formation, whereas the retention of one deuterium atom is indicative of the formation of metabolite IIa through GSH conjugation of either 2,3-dibromopropanal or 2-bromo-3-chloropropanal. These data indicate that IIa is a marker metabolite for the potent direct-acting mutagen, 2-BA, or its metabolic precursors 2,3-dibromopropanal or 2-bromo-3-chloropropanal. Therefore, evidence has been presented for bioactivation of DBCP by glutathione and cytochrome P450 mediated mechanisms.

Acetylcysteine↗