Increased CYP3A4 Activity Research Articles

Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test.

After evaluating a patient who appeared to have a falsely abnormal response to the dexamethasone suppression test while taking troglitazone, we examined the effects of troglitazone on the activity of hepatic CYP3A4 and the screening tests for Cushing's syndrome. We studied five healthy women and three healthy men, aged 25 +/- 2 yr, before and after treatment with troglitazone (600 mg daily) for 28 d. Baseline 0800 h cortisol and corticosterone were similar before and after troglitazone treatment. Before troglitazone treatment, all subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 0.66 +/- 0.08 micro g/dl) during the 1-mg overnight dexamethasone suppression test (DST), whereas during troglitazone treatment none of the subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 9.0 +/- 1.8 micro g/dl). Serum dexamethasone levels decreased by 66 +/- 4%, and the erythromycin breath test measurements increased by 27 +/- 8%, indicating increased CYP3A4 activity during troglitazone treatment. The hydrocortisone suppression test (HST) was performed by administering 50 mg hydrocortisone at 2300 h. Using the criterion of suppression of 0800 h plasma corticosterone by more than 50%, the specificity of the HST was 100% both before and after troglitazone treatment. In conclusion, troglitazone induced the activity of CYP3A4 leading to falsely abnormal DST. HST is a useful alternative to the DST in patients taking medications that increase the activity of CYP3A4.

Urinary 6 beta-hydroxycortisol excretion in Hong Kong Chinese patients with hepatocellular carcinoma and other chronic liver diseases.

The biotransformation of xenobiotics into toxic metabolites by cytochrome P-450 has been implicated in carcinogenesis. This study investigated CYP3A4 activity, which metabolically activates procarcinogens such as aflatoxin B1, by measuring the urinary 6 beta-hydroxycortisol (6 beta OHF) to free cortisol (F) ratio in patients with hepatocellular carcinoma (HCC) and other chronic liver diseases. One hundred forty-three controls and 150 patients with different liver diseases, including chronic liver disease (due to alcoholism and/or chronic hepatitis B virus infection), cirrhosis (any cause), and resectable and nonresectable HCC, were recruited. Twenty-four hour urine samples were collected for measurement of 6 beta OHF and free cortisol by an enzyme-linked immunosorbent assay (ELISA) and a radioimmunoassay, respectively. Patients with nonresectable HCC showed a significant increase in 6 beta OHF excretion as well as their 6 beta OHF/F ratio (P < 0.05) when compared with the controls and other liver disease groups including patients with resectable HCC. The nonresectable HCC group showed a bimodal distribution in the 6 beta OHF/F ratio. Using a ratio of 9 or more in all HCC patients, the sensitivity and specificity of using the 6 beta OHF/F ratio to predict nonresectability of HCC was 48.8% and 92.6%, respectively. Our results show an increase in mean CYP3A4 enzyme activity, reflected as an increase in the 6 beta OHF/F ratio, in Hong Kong Chinese with nonresectable HCC compared with those with resectable HCC and other liver diseases. Although the role of increased CYP3A4 activity in the aetiology of HCC is not known, our specificity and sensitivity estimates suggest that a high 6 beta OHF/F ratio indicates probable inoperability. However, a normal level is a poor predictor of resectability.