In previous work, we showed that o-quinones (3,5-cyclohexadiene-1,2-diones) can isomerize to p-quinone methides (4-alkyl-2,5-cyclohexadien-1-one) at rates which depend on the type of substituent at the para position [Iverson, S. L., Hu, L. Q., Vukomanovic, V., and Bolton, J. L. (1995) Chem. Res. Toxicol. 8, 537-544]. In the present investigation, we explored the mechanism of this isomerization reaction using 4-propyl-3,5-cyclohexadiene-1,2-dione (PQ) and its benzyl dideuterio analog 4-(1',1'-dideuteriopropyl)-3,5-cyclohexadiene-1, 2-dione (DPQ). The results show that the isomerization reaction is general base-catalyzed, which suggests that amino acids on proteins with basic side chains could catalyze the reaction in vivo. The Bronsted beta value was determined to be 0.23 +/- 0.02, consistent with the transfer of a proton in the rate-determining step. The rate/pH profile generated from the buffer dilution plots showed dependence on hydroxide ion concentration from pH 7.8 to 9, indicative of base catalysis. From pH 6 to 7.8, the reaction was independent of pH, suggesting that other processes compete at low buffer concentration in this pH region. Substitution of the benzyl CH2 group with CD2 dramatically slows the isomerization reaction. The kinetic deuterium isotope effect on quinone methide formation was determined by measuring the amount of quinone methide trapped as GSH conjugates from PQ compared with DPQ. The isotope effect on product formation was 5.5 +/- 0.6, 37 degrees C. These data provide further evidence that formation of these electrophilic quinone methides from o-quinones could be catalyzed by basic residues in vivo and that the reaction could be inhibited by deuterium substitution at the benzyl methylene group.

Alkylation↗

PubMedDate not supplied

The locus of sequence-directed and protein-induced DNA bending.

The bending locus of trypanosome kinetoplast DNA, identified by gel electrophoresis, has tracts of a simple repeat sequence (CA5-6 T) symmetrically distributed about it, with a repeat interval of 10 base pairs. The analogous bending induced when catabolite gene activating protein binds to its recognition sequence near the promoter of the Escherichia coli lac operon is centred on a site about 5-7 base pairs away from the centre of the protein binding site.

Animals↗

PubMedDate not supplied

DNA bending at adenine . thymine tracts.

Intrinsic bending of DNA molecules results from local structural polymorphism in regions of homopolymeric dA . dT which are at least 4 base pairs long; the A . T tracts must be repeated in phase with the helix screw. Bending, in the direction of base-pair tilt rather than roll, occurs at the junctions between the A . T tract and adjacent B-DNA, with a larger angle at the 3' than at the 5' end of the A tract.

Adenine↗

PubMedDate not supplied

Leigh syndrome presenting with dystonia: report of one case.

A 22-month-old female presented with developmental delay and dystonia. The T2 weighted image of the brain MRI showed bilateral symmetrical high signal lesions over the putamen. An increased serum lactate pyruvate ratio (29.25) and a positive oral glucose lactate stimulation test were noted. Electron microscopic examination showed abnormal mitochondrial aggregation with band cristae in the subsarcolemmal area. These findings were indicative of clinical Leigh's syndrome. However, unusually the mt DNA analysis showed a point mutation at the nucleotide position 8344.

DNA, Mitochondrial↗

PubMedDate not supplied

Serum trace elements, glutathione, copper/zinc superoxide dismutase, and lipid peroxidation in epileptic patients with phenytoin or carbamazepine monotherapy.

Disturbance of metabolism of trace elements and antioxidants are investigated in epileptic patients with long-term therapy of anticonvulsants. One hundred and fifteen subjects including healthy controls, untreated epileptic patients, and phenytoin (PHT)- or carbamazepine (CBZ)-treated epileptic patients were recruited in this study. Serum malondialdehyde was measured as an index of extracellular lipid peroxidation. The levels of serum copper (S-Cu), serum zinc, copper/zinc superoxide dismutase (CuZn-SOD), and reduced glutathione in the serum were monitored simultaneously. The results showed that malondialdehyde, S-Cu, and CuZn-SOD levels in the serum all were significantly increased, but the glutathione level was significantly decreased, in all the epileptic patients with PHT monotherapy compared with those of the controls. However, no significant differences of these parameters in the epileptic patients with CBZ monotherapy were found except for a mild elevation of the activity of serum CuZn-SOD. We conclude that compared with PHT monotherapy, the CBZ monotherapy induced less disturbance in trace element metabolism, antioxidants, and lipid peroxidation in the serum of epileptic patients.

Adult↗

PubMedDate not supplied

Radiosurgery as a treatment alternative for dural arteriovenous fistulas of the cavernous sinus.

PURPOSE: Radiosurgery is an effective treatment for cerebral arteriovenous malformations. We conducted the present study to investigate the feasibility and efficacy of gamma knife radiosurgery for dural arteriovenous fistulas (DAVFs) of the cavernous sinus. METHODS: Eighteen patients (12 women and six men; 29-75 years old [mean age, 55 years]) with DAVFs of the cavernous sinus (Barrow's type B:1, C:7, and D:10) treated by gamma knife radiosurgery were enrolled in the study. DAVFs were bilateral in six patients and unilateral in 12. Stereotactic X-ray angiography and MR imaging were performed for targeting the radiosurgery. Areas of arteriovenous communication targeted for irradiation were first outlined on the X-ray angiograms. The target regions were then transferred to and displayed on the MR images. Dose planning was based on findings on the integrated images. Prescribed maximum target doses were 22 to 38 Gy (mean, 28 Gy). The targets were covered by 50% to 90% isodose levels. Radiation doses to the surrounding optic apparatus were kept to less than 8 Gy. The patients were followed up with color Doppler sonography and MR imaging. When noninvasive imaging suggested obliteration, X-ray angiography was performed to verify the results. RESULTS: The DAVFs were totally obliterated in 12 (80%) of the 15 patients. In the other three, one was almost completely obliterated at 14 months and two were partially obliterated at 19 and 27 months, respectively, after radiosurgery. No complications or symptom worsening occurred during the follow-up period. CONCLUSION: Gamma knife radiosurgery is a feasible, effective, and safe treatment for DAVFs of the cavernous sinus. Integration of stereotactic X-ray angiography and MR imaging not only aids treatment efficacy but also protects the relevant vital structures, especially the optic apparatus, from the hazards of radiation.

Adult↗