N-acetyl-p-benzoquinone imine (NAPQI) has been proposed as the toxic metabolite of acetaminophen for the past 10 years, although it has never been detected as an enzymatic oxidation product of acetaminophen. We report (i) direct detection of NAPQI formed as an oxidation product of acetaminophen by cytochrome P-450 and cumene hydroperoxide and (it) indirect evidence that is compelling for NAPQI formation from acetaminophen by cytochrome P-450, NADPH, and NADPH-cytochrome P-450 reductase. Evidence is provided for the rapid reduction of NAPQI back to acetaminophen by NADPH and NADPH-cytochrome P-450 reductase such that steady-state levels of NAPQI were below our detection limits of 6.7 X 10-8 M. In mouse liver microsomal incubations, radiolabeled analogs of both NAPQI and acetaminophen bound covalently to microsomal protein with the loss of -20% of the acetyl group as acetamide. The binding in each case was decreased by glutathione with concomitant formation of 3-Sglutathionylacetaminophen. The binding also was decreased by L-ascorbic acid, NADPH, and NADH with reduction of NAPQI to acetaminophen. Results of partitioning experiments indicate that NAPQI is a major metabolite of acetaminophen, a considerable fraction of which is rapidly reduced back to acetaminophen.The widely used analgesic-antipyretic drug acetaminophen is known to cause serious liver necrosis at high doses in man and experimental animals (1, 2). An electrophilic product of cytochrome P-450 oxidation that depletes cellular glutathione (GSH) and covalently binds to tissue macromolecules has been implicated in this toxic reaction (3). Initially, the formation of the arylating metabolite was believed to involve N-oxidation of acetaminophen to N-hydroxyacetaminophen followed by dehydration to N-acetyl-p-benzoquinone imine (NAPQI) (4). However, subsequent kinetic studies and carrier pool trapping experiments in vitro (5, 6) and metabolism studies of N-hydroxyacetaminophen in vivo (7) have shown that if N-hydroxyacetaminophen is an intermediate, it must decompose at the enzymatic site of hydroxylation.Although it appears that N-hydroxyacetaminophen is not significantly involved in acetaminophen toxicity, evidence still favors NAPQI as an ultimate toxin. We recently synthesized NAPQI in pure crystalline form, and studies have shown this reactive quinoneimine to be highly toxic in mice and to isolated hepatocytes (8). Other investigators, using aqueous solutions of NAPQI generated either electrochemically (9) or by dehydration of N-hydroxyacetaminophen (7, 10, 11), have shown NAPQI to be an electrophile and an oxidant. Similar properties were exhibited by stable benzene solutions of chemically synthesized NAPQI (12).We present in this report direct evidence for the formation of NAPQI from acetaminophen in incubations of acetaminophen with cumene hydroperoxide (CHP) and hepatic cytochrome P-450 purified from phenobarbital-pretreated rats. Similar attempts to directly detect NAPQI in incubations of acetaminophen with either purified P-450, NADPH, and...

The U.S. Department of Energy's National Energy Technology Laboratory (NETL) located in Albany, OR (formerly the Albany Research Center) has studied ex situ mineral carbonation as a potential option for carbon dioxide sequestration. Studies focused on the reaction of Ca-, Fe-, and Mg-silicate minerals with gaseous CO2 to form geologically stable, naturally occurring solid carbonate minerals. The research included resource evaluation, kinetic studies, process development, and economic evaluation. An initial cost estimate of approximately $69/ton of CO2 sequestered was improved with process improvements to $54/ton. The scale of ex situ mineral carbonation operations, requiring 55 000 tons of mineral to carbonate, the daily CO2 emissions from a 1-GW, coal-fired power plant, may make such operations impractical.

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A series of 111 mesenchymal chondrosarcomas was reviewed. The ages of the patients ranged from 5 to 74 years, and approximately 60% of them were in the second and third decades of life. There was no significant sex predilection. Seventy-two tumors, including 5 that involved multiple skeletal sites, arose in bone. Thirty-eight tumors were found in extraskeletal sites. At initial diagnosis, multifocal involvement, both in bone and in soft tissue, was observed in one case. Roentgenographically, the lesions in bone frequently resembled ordinary chondrosarcomas, showing osteolytic and destructive appearances with stippled calcification. Tumors in extraskeletal sites were almost always identified as calcified masses. Histologically, a combination of cellular zones composed of undifferentiated small cells and chondroid zones typically presented a bimorphic appearance that was virtually pathognomonic in most cases. Ablative surgical treatment seemed to be the procedure of choice. The value of irradiation or chemotherapy (or both) was difficult to assess in the current study. Prognosis for patients with mesenchymal chondrosarcoma is usually poor, and long-term follow-up is necessary. In a group of 23 patients from the Mayo Clinic, the 5-year survival rate was 54.6% and the 10-year survival rate was 27.3%.

This study of 195 patients with giant‐cell tumor reemphasizes the female predominance, the predilection for the region of the knee, and the extreme rarity of the tumor in patients with immature skeletons. One of the tumors occurred in a patient with Paget's disease of bone. There were 2 patients with 2 giant‐cell tumors each. Surgical treatment short of complete resection or amputation was followed by recurrence of benign giant‐cell tumor in 44.6% of cases. Adjunctive radiation or cautery did not decrease this rate. Primary en bloc resection or amputation was uniformly curative. Primary radiation therapy had very limited value. Sarcomas developed in 17 patients (8.7%) of the total; these lesions we have called malignant giant‐cell tumors. In 4 instances, zones of anaplastic sarcoma were found in otherwise typical giant‐cell tumors. The remaining 13 sarcomas were found in recurrent tumors, and in 11 of these, the primary treatment had included radiation. The evidence indicates that surgical removal is the best treatment and that radiation should be employed only for tumors that are unresectable because of their location.