Biomedical subjects
Publications and source records attributed to S D Nelson.
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BACKGROUND: Recurrent abdominal sarcomas have an extremely high rate of recurrence and poor overall survival. A prospective study was initiated to assess the feasibility, toxicity, and benefit of surgical resection and intraperitoneal chemotherapy for improving local control of disease and overall survival. METHODS: Fifty-four patients underwent surgical excision of all gross disease and postoperative intraperitoneal chemotherapy with mitoxantrone. Thirty-five patients had peritoneal disease only (stage II), and 19 patients had peritoneal disease with hepatic metastases (stage III). RESULTS: Nine (17%) patients remain free of disease with a mean follow-up of 37 months. The remaining 45 patients (83%) have had recurrence, with a mean interval to recurrence of 11 months. Stage (P = .001) and grade (P = .005) were the only two variables found to significantly affect recurrence. There was an overall peritoneal recurrence rate of 48% and an overall hepatic failure rate of 69%. Nineteen (35%) of the patients are alive, with a mean follow-up of 46 months. The overall 5-year survival was 31%. The 5-year survival for stage II patients was 46%; for stage III patients, it was only 5%. Stage (P = .001) and grade (P = .056) were the only two variables found to significantly affect survival. There were no treatment-related deaths, and only 5 patients (9%) developed local complications. CONCLUSIONS: Aggressive surgical resection and intraperitoneal chemotherapy for recurrent abdominal sarcomas is a feasible treatment approach with minimal toxicity. Although this treatment had little effect on the hepatic spread of this disease and thus overall survival, it appears to have significantly lowered the rate of peritoneal recurrence and may provide a survival benefit for patients with disease limited to the peritoneum.
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Highly purified isozymes of cytochrome P-450 catalyzed the formation of 3-glutathion-S-ylacetaminophen (GS-APAP) and 3-hydroxyacetaminophen (3-OH-APAP) from acetaminophen (APAP). A major isozyme from untreated male rats (P-450UT-A) catalyzed the formation of ca. 2.0 nmol/nmol of P-450/10 min of 3-OH-APAP and approximately 7.2 nmol of GS-APAP/nmol of P-450/10 min. Antibodies specific for cytochrome P-450UT-A caused a decrease in the amounts of both metabolites produced in microsomal incubations. In contrast to these results, two other constitutive P-450 isozymes from rat liver, cytochrome P-450UT-F and the female specific isozyme P-450UT-I, produced less of both oxidative metabolites. Moreover, they produced significantly more of the catechol metabolite than the glutathione conjugate. These results are in accord with the observation that male rats are more susceptible to acetaminophen hepatotoxicity than female rats. Isozymes induced by phenobarbital also produced more of the catechol than the glutathione conjugate. Conversely, the major isozyme induced by beta-naphthoflavone, cytochrome P-450 beta NF-B, produced a significantly greater amount of GS-APAP than 3-OH-APAP. When comparison was made to a major phenobarbital inducible form (cytochrome P-450PB-B) a definite isozyme specificity for the formation of the two metabolites was seen. The catechol was formed at rates of 2.21 and 0.53 nmol/nmol of P-450/10 min by cytochromes P-450PB-B and P-450 beta NF-B, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
3'-Hydroxyacetanilide (AMAP) is a nonhepatotoxic regioisomer of acetaminophen (APAP) that nonetheless does form reactive metabolites which bind to hepatic proteins. Because differences in the nature of reactive metabolites formed from AMAP and APAP may explain differences in their propensity to cause hepatotoxicity, characterization of the reactive metabolites of AMAP was undertaken. The naturally occurring sulfhydryl-containing tripeptide glutathione (GSH) was used to trap the reactive metabolites. Four mono-GSH conjugates and one di-GSH conjugate of oxidative AMAP metabolites were characterized by 1H NMR and soft ionization (LSIMS or FAB) mass spectral techniques, as well as by comparison of liquid chromatographic and spectral characteristics with synthetic standards. Two isomeric mono-GSH conjugates of 2-acetamidohydroquinone (2-AcHQ) are formed as well as a bis-GSH conjugate. A mono-GSH conjugate of 3',4'-dihydroxyacetanilide (3-OH-APAP) also was formed. Thus, these GSH conjugates most likely arise by reaction of GSH with 2-acetamido-p-benzoquinone (2-APBQ) and 4-acetamido-o-benzoquinone (4-AOBQ), respectively, as oxidation products of the known AMAP metabolites 2-AcHQ and 3-OH-APAP. Finally, a GSH conjugate of 3'-methoxy-4'-hydroxy-acetanilide (3-OMe-APAP) was detected in bile of mice administered AMAP. This conjugate probably arises by oxidation of 3-OMe-APAP, another known metabolite of AMAP. The presumed oxidation product, N-acetyl-3-methoxy-p-benzoquinone imine (MAPQI), was synthesized and found to react with GSH to give the same GSH conjugate as that detected in bile and in incubations of 3-OMe-APAP with mouse liver microsomes plus GSH.(ABSTRACT TRUNCATED AT 250 WORDS)
The cytotoxicity of acetaminophen (paracetamol) has been shown to be associated with a disruption of intracellular Ca2+ homeostasis caused by the interaction of its metabolite N-acetyl-p-benzoquinone imine (NAPQI) with hepatocyte thiols [Moore, M., et al. (1985) J. Biol. Chem. 260, 13035-13040]. Inasmuch as NAPQI can both covalently bind to thiols and oxidize thiols, we investigated the effects of two dimethylated analogues of NAPQI, one of which (2,6-dimethyl-NAPQI) primarily binds to thiols and the other of which (3,5-dimethyl-NAPQI) primarily oxidizes thiols. Of the three compounds, 2,6-dimethyl-NAPQI decreased protein thiols to the greatest extent and also inhibited hepatocyte plasma membrane Ca(2+)-ATPase to the greatest extent. The 3,5-dimethylated analogue decreased protein thiols to the least extent and inhibited the plasma membrane Ca(2+)-ATPase to a lesser extent. The cytotoxicity of all three compounds was preceded by a sustained elevation in cytosolic Ca2+ as compared to the transient rise caused by the alpha-agonist phenylephrine. Again, the 2,6-dimethyl analogue was the most potent of the three compounds. The thiol reagent dithiothreitol (DTT), which reversed the inhibition of the Ca(2+)-ATPase and the rise in cytosolic Ca2+, also protected against cytotoxicity. Agents that are known to inhibit either Ca(2+)-dependent proteases or phospholipases significantly delayed the onset of cytotoxicity caused by NAPQI and its analogues. Our results suggest that both arylation and oxidation of protein thiols may result in the elevation of cytosolic Ca2+ and in cytotoxicity and that arylation of critical thiol groups appears to be the more lethal reaction.
Pulegone, a naturally occurring hepatotoxin, is metabolically activated to chemically reactive intermediates that are capable of covalent binding to cellular protein. Studies in vivo and in vitro with inhibitors and inducers of cytochrome P-450 demonstrated an association among the hepatocellular toxicity of pulegone and its metabolic activation and covalent binding to protein. The exocyclic double bond of pulegone apparently is an important structural feature in the activation mechanism and binding to protein inasmuch as the reduced analogue, menthone, is neither hepatotoxic nor does it bind extensively to tissue proteins. Preliminary studies using semicarbazide as a trapping agent indicate that an unsaturated gamma-ketoaldehyde is the ultimate chemically reactive metabolite of pulegone.
1,2-Dibromo-3-chloropropane (DBCP), a haloalkane nematocide and soil fumigant, is metabolically activated to chemically reactive species that are direct-acting mutagens in a Salmonella typhimurium TA 100 test system. Studies in vitro with rat liver microsomes indicated that oxidation at carbon 3 resulted in the formation of an unstable gem-chlorohydrin that rearranged with elimination of hydrogen bromide to form (Z)-2-chloro-3-(bromomethyl)oxirane [(Z)-CBPO] and (E)-2-chloro-3-(bromomethyl)oxirane [(E)-CBPO]. Gas chromatography-mass spectrometry (GC-MS) with positive ion chemical ionization (CI) was employed to identify (Z)-CBPO and (E)-CBPO by comparison of characteristic fragment ions in their CI mass spectra with those observed for authentic standards. Quantitative GC-MS methodology was exploited to quantitate the rate of formation of (Z)-CBPO and (E)-CBPO from DBCP and analogues of DBCP specifically deuterated at carbon 1 and carbon 3. The rate of formation of Z- and E-isomers of CBPO was 31 and 33 pmol/(min.mg of protein), respectively, from DBCP; substitution with deuterium at carbon 1 increased the rate of epoxide formation by 50%, whereas CBPO formation could not be detected from a substrate labeled with deuterium at carbon 3. Both epoxides were directly acting mutagens to S. typhimurium TA 100. (Z)-CBPO caused approximately twice as many his+ revertants/nmol compared to (E)-CBPO. Oxidation at carbon 2 of DBCP resulted in the formation of a bifunctional alkylating agent, 1-bromo-3-chloroacetone, presumably via the intermediacy of an unstable gem-bromohydrin.(ABSTRACT TRUNCATED AT 250 WORDS)