Acetylator genotype-dependent metabolic activation of carcinogenic N-hydroxyarylamines by S-acetyl coenzyme A-dependent enzymes of inbred hamster tissue cytosols: relationship to arylamine N-acetyltransferase

A genetic polymorphism in S-acetyl coenzyme A (AcCoA)-dependentN-acetyltransferase has been associated with a differentialrisk for certain cancers in humans. In this study, several tissuesfrom the inbred Syrian hamster with a genetically defined AcCoA-dependentN-acetyltransferase polymorphism (homozygous rapid acetylator,Bio. 87.20; homozygous slow acetylator, Bio. 82.73/H; and heterozygousacetylator, Bio. 87.20 x Bio. 82.73/H F₁), were investigatedfor the relationship of arylamine N-acetyltransferase to theAcCoA-dependent metabolic activation of carcinogenic N-hydroxy(N-OH)-arylamines to bind to DNA (O-acetyltransferase). Thelevels of both 2-aminofluorene (AF) N-acetyltransferase andN-OH-AF O-acetyltransferase activity reflected the N-acetylatorgenotype in liver, intestine, kidney and lung cytosols. A significantacetylator gene—dose response for AF N-acetyltransferaseand N-OH-AF O-acetyltransferase activities was observed in liverand lung cytosols. In contrast, acetylator genotype was notconsistently expressed for the AcCoA-dependent N-acetylationof 4-aminobiphenyl (ABP), nor for the AcCoA-dependent metabolicactivation of N-OH ABP and N-OH-3,2'-dimethyl-4-aminobiphenylin these me tissue cytosols. Two peaks of acetyltransferaseactivity were partially purified by ion exchange FPLC chromatographyfrom the hepatic cytosol of both the homozygous rapid and homozygousslow acetylator hamster. In contrast to unfractionated cytosol,the isozyme(s) eluting first clearly demonstrated levels ofAcCoA-dependent arylamine N-acetyltransferase and N-OH-arylamineO-acetyltransferase activities that were consistent with N-acetylatorgenotype (polymorphic) for all substrates tested. In contrast,the slower eluting isozyme(s) in each acetylator cytosol showedlevels of AcCoA-dependent N-and O-acetyltransferase activitiesthat did not vary with N-acetylator genotype (monomorphic).The AcCoA-dependent O-acetyltransferase activity of both themonomorphic and polymorphic peaks was paraoxon resistant. Thesestudies demonstrate acetylator genotype-dependent control ofAcCoA-dependent metabolic activation of N-OH-arylamines(O-acetylation)by polymorphic isozyme(s) similar to that for AcCoA-dependentN-acetylation of arylamines in the hamster. The polymorphicgenetic control of N-OH arylamine O-acetyltransferase may bean important risk factor for arylamine-induced cancer, in thosespecies and tissues expressing appreciable levels of O-acetyltransferaseactivity.     

Radical forequarter amputation with hemithoracectomy and free extended forearm flap: Technical and physiologic considerations

Background: A radical forequarter amputation with partial chest wall resection (one to four ribs) has been reported for benign and malignant lesions involving the shoulder and chest wall region. Concerns about reconstruction and postoperative pulmonary function have previously limited more extensive chest wall resections. The current report describes the first case in which a complete unilateral anterior and posterior chest wall resection and pneumonectomy (hemithoracectomy) accompany a forequarter amputation. A novel reconstructive technique used the full circumference of the forearm tissue with an intact ulna as a free osseomyocutaneous flap. Methods: In this case, a 21-year-old patient presented with an extensive recurrent desmoid tumor that involved the shoulder, brachial plexus, subclavian vein, and chest wall from the lateral sternal border to the midportion of the scapula and down to the eighth rib. The operative technique involved removal of the entire right hemithorax from the midline sternum to the transverse process posteriorly, down to the ninth rib inferiorly. Due to the absence of a rigid hemithorax, the uninvolved ipsilateral lung was also removed. The forearm flap was prepared before final separation of the specimen and division of the subclavian vessels. Results: Postoperatively, the patient maintained excellent oxygenation without atelectasis or fever and was extubated on the 15th postoperative day. As expected after pneumonectomy, significant decreases from preoperative to immediate postoperative values were noted for the vital capacity (VC) (from 4.87 L to 1.29 L), forced 1-s expiratory volume (FEV1) (from 3.77 L to 1.02 L), and inspiratory capacity (IC) (3.33 1 to 0.99 1). Rehabilitation included a specially designed external prosthesis to provide cosmesis and prevent scoliosis. By the 15th postoperative week the patient had returned to normal social and physical activities, with a gradual improvement in all respiratory parameters: VC 1.52 L, FEV1 1.29 L, IC 1.04 L. There has been no evidence of tumor recurrence at 1 year. Conclusions: This report provides evidence that a complete hemithoracectomy, pneumonectomy, and forequarter amputation can be safely performed for selective tumors involving the shoulder region with extensive chest wall invasion. Reconstruction may be achieved with an extended forearm osseomyocutaneous free flap with an excellent functional outcome. Presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.