Evaluation of serum human telomerase reverse transcriptase as a novel marker for cervical cancer.

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of human telomerase and its rate-limiting component. The purpose of the present study was to investigate the diagnostic value of hTERT in serum of cervical cancer patients. Preoperative values of hTERT, squamous cell carcinoma antigen (SCC-ag) and cancer antigen 125 (CA 125) were measured by enzyme-linked immunosorbent assay (ELISA) in 192 patients with squamous cell carcinoma or adenocarcinoma of the uterine cervix and 38 healthy controls. Elevated pretreatment levels of hTERT were identified in 80.2% of squamous cell carcinoma and 73.8% of adenocarcinoma patients. The expression of serum hTERT was correlated with telomerase activity in cancer tissues of both histological types. Pretreatment serum hTERT levels showed a significant correlation with clinical stage, tumor size and lymph node metastasis, but not with age. Serum hTERT measurement was found to be useful in the diagnosis and assessment of clinical stage of cervical cancer, and to be superior to the conventional tumor markers. Therefore, serum hTERT is a novel and readily available marker for cervical malignancies.

Enhanced xenobiotic-induced hepatotoxicity and Kupffer cell activation by restraint-induced stress.

We tested the hypothesis that environmental stress is a predisposing factor for liver injury by examining the effect of acute restraint on liver injury provoked by carbon tetrachloride (CCl4) and allyl alcohol. Mice were immobilized using Plexiglas restraint cages, producing a form of psychogenic stress, whereas other animals were allowed to roam free. Serum alanine aminotransferase levels were elevated significantly in restrained animals after administration of varying doses of CCl4 or allyl alcohol that did not produce liver injury in unrestrained animals. This enhanced liver injury after CCl4 was seen in both male and female mice. The duration of acute restraint was found to be important because a period of 2.5 h of restraint enhanced hepatotoxicity, whereas shorter periods of restraint did not significantly increase liver injury. Serum corticosterone concentrations increased, whereas hepatic glutathione content decreased during and after acute restraint. In addition, delay in administration of CCl4 until 5 h after completion of restraint also produced an elevated level of liver injury compared with that seen in free roaming animals. Immunohistochemical examination of the livers showed significantly enhanced Kupffer cell activation in restrained mice compared with that of free roaming mice. These observations suggest that induction of psychogenic stress may increase the susceptibility to liver injury observed with classic hepatotoxicants and may represent an important predisposing factor to liver injury after xenobiotic exposure. The underlying mechanism seems to be increased macrophage activation in the liver, which may subsequently sensitize hepatocytes to xenobiotics and thus enhance hepatotoxicity.

Hepatic enzymatic synthesis and hydrolysis of CoA esters of solvent-derived oxa acids.

Many ethylene glycol-derived solvents are oxidized to xenobiotic alkoxyacetic acids (3-oxa acids) by hepatic enzymes. The toxicity of these ubiquitous solvents has been associated with their oxa acid metabolites. For many xenobiotic carboxylic acids, the toxicity is associated with the CoA ester of the acid. In this study, related alkoxyacetic acids were evaluated as potential substrates for acyl-CoA synthetases found in mitochondrial, peroxisomal, and microsomal fractions isolated from rat liver. Likewise, chemically synthesized oxa acyl-CoAs were used as substrates for acyl-CoA hydrolases associated with the same rat liver fractions. Activities of the xenobiotic oxygen-substituted substrates were compared with analogous physiologic aliphatic substrates by UV-vis spectrophotometric methods. All of the solvent-derived oxa acids were reasonable substrates for the acyl-CoA synthetases, although their activity was usually less than the corresponding physiologic acid. Acyl-CoA hydrolase activities were decreased compared with acyl-CoA synthetase activities for all substrates, especially for the oxa acyl-CoAs. These studies suggest that these xenobiotic carboxylic acids may be converted to reactive acyl-CoA moieties which will persist in areas of the cell proximal to lipid synthesis, beta-oxidation, protein acylation, and amino acid conjugation. The interaction of these xenobiotic acyl-CoAs with those processes may be important to their toxicity and/or detoxification.