No abstract

Endogenous cellular oxidation of omega6-polyunsaturated fatty acids (PUFAs) has long been recognized as a contributing factor in the development of various cancers. The accrual of DNA damage as a result of reaction with free radical and electrophilic aldehyde products of lipid peroxidation is believed to be involved; however, the genotoxic and mutation-inducing potential of specific membrane PUFAs remains poorly defined. In the present study we have examined the ability of peroxidizing arachidonic acid (AA, 20:4omega6) to induce DNA strand breaks, base modifications, and mutations. The time-dependent induction of single-strand breaks and oxidative base modifications by AA in genomic DNA was quantified using denaturing glyoxal gel electrophoresis. Mutation spectra were determined in XP-G fibroblasts and a repair-proficient line corrected for this defect by c-DNA complementation (XP-G(+)). Mutation frequencies were elevated from approximately 5- to 30-fold over the background following reaction of DNA with AA for various times. The XPG gene product was found to be involved in the suppression of mutations after extended reaction of DNA with AA. Arachidonic acid-induced base substitutions were consistent with the presence of both oxidized and aldehyde base adducts in DNA. The frequency of multiple-base substitutions induced by AA was significantly reduced upon correction for the XPG defect (14% vs 2%, P = 0.0015). Evidence is also presented which suggests that the induced frequency of multiple mutations is lesion dependent. These results are compared to published data for mutations stimulated by alpha,beta-unsaturated aldehydes identified as products of lipid peroxidation.

Vasopressin is a major determinant of vascular tone during cardiac surgery however vasopressin levels are unknown in patients presenting for pulmonary thromboendarterectomy (PTE) utilizing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). We performed an observational study in 22 patients with chronic thromboembolic disease undergoing PTE with CPB and DHCA to assess perioperative vasopressin levels. Serum vasopressin levels were assessed using a radioimmunoassay at: 1. baseline before surgery, 2. after anesthetic induction, 3. during CPB, 4. after DHCA, 5. after CPB. In 8 patients, vasopressin was undetectable (< 0.5 pg/mL) at baseline. Vasopressin before and after induction of anesthesia was 1.06 +/− 0.96 (SD) pg/mL and 1.21 +/− 1.54 pg/mL, respectively. During CPB, vasopressin increased to 19.22 +/− 28.22 pg/mL (a 2–30‐fold increase from baseline). Vasopressin remained elevated after DHCA (16.29 +/− 22.71 pg/mL) and after CPB (23.619 +/− 26.29 pg/mL). There were no differences between vasopressin levels during CPB, after DHCA, or after CPB. We conclude that a significant portion of these patients may present for PTE with a relative deficiency of vasopressin. Nevertheless, there is a marked increase from baseline in the secretion of vasopressin at the initiation of CPB and thereafter. Further studies are required to determine if vasopressin secretion in this population is abnormal.