Reduced urinary 6β-hydroxycortisol to cortisol ratios in patients with liver cirrhosis
Introduction
Urinary 6β-hydroxycortisol (6β-HC) to free cortisol (C) ratio may be a useful non-invasive parameter of the hepatic cytochrome P450 (CYP) activity in humans [1], [2]. Earlier studies [3], [4] demonstrated that the urinary 6β-HC/C ratios (or 6β-HC excretion) is a good index for the enzyme induction of CYP isoforms by concomitant medications: several CYP inducers (e.g. rifampicin, phenobarbital) produced a substantial increase in the urinary 6β-HC/C ratios (or 6β-HC excretion) in patients and healthy subjects as compared with their respective pretreatment values. Subsequently, Ged et al. [5] reported that the in vitro metabolism of C to 6β-HC with human liver microsomes is mediated mainly by CYP3A and that there was a highly significant (r=0.81, P<0.001) correlation between the urinary 6β-HC/C ratio and CYP3A levels quantitated immunologically in liver biopsy specimens. Thus, the urinary 6β-HC/C ratio has been considered as a useful parameter of in vivo CYP3A induction [2].
However, debate continues whether the urinary 6β-HC/C ratio would also be a useful parameter for detecting reduction of hepatic CYP3A4 activity. Watkins et al. [6] showed that there was a highly significant correlation between the results obtained from erythromycin breath tests (an established marker of the hepatic CYP3A4 activity) and urinary 6β-HC/C ratios in healthy subjects. In addition, several studies [7], [8], [9], [10] demonstrated that a single or repeated administration of competitive or mixed-type CYP3A4 inhibitors (i.e. cimetidine, methadone, fluconazole, nelfinavir and nelfinavir plus ketoconazole, clarithromycin) significantly reduced the 6β-HC/C ratio and/or 6β-HC excretion measured in 4- or 24-h urine samples in healthy subjects. In addition, we have recently reported that clarithromycin, a potent CYP3A4 inhibitor, significantly inhibits the partial cortisol clearance by 6β-hydroxycortisol formation in a dose-dependent manner during Helicobacter pylori eradication therapy with a combination of clarithromycin–lansoprazole–amoxicillin in patients with H. pylori-positive peptic ulcer diseases [11]. In contrast to these data, Watkins et al. [6] found only inconsistent changes in the urinary 6β-HC/C ratio in four healthy subjects who were given a single oral dose (250 mg) of another CYP3A inhibitor, troleandomycin.
Another approach for clarifying the contribution of the hepatic CYP3A4 activity to urinary 6β-HC/C ratios is to compare this parameter between patients with liver diseases and healthy subjects. Watkins et al. [6] reported that a recipient of liver transplantation exhibited a 50% reduction in the urinary 6β-HC/C ratio during the anhepatic period of the surgery, indicating that at least some 50% of 6β-HC in urine sample was associated with the hepatic CYP3A metabolism. In contrast, Ng et al. [12] showed that the mean urinary 6β-HC/C ratio obtained from patients with liver cirrhosis differs insignificantly from that obtained from liver disease-free controls. They also reported that the mean 6β-HC/C ratio obtained from patients with unresectable hepatocellular carcinoma was significantly greater than that obtained from the controls. At present, their data have not been confirmed by others. Because they employed an immunoassay method that might have been less specific to urinary 6β-HC and C than currently employed HPLC methods [13], [14], we considered that a reappraisal of urinary 6β-HC/C ratios in patients with liver diseases as compared with healthy subjects is to be warranted. Here, we present the data that support a significant association of hepatic CYP3A activity with the urinary 6β-HC/C ratio.
Section snippets
Materials and methods
Urine samples were collected for 24 h in 12 patients with chronic hepatitis, 15 patients with liver cirrhosis and 12 healthy subjects. Urine collection was begun at 07:00 h on the study day and was continued until 07:00 h on the next day. The diagnosis of liver cirrhosis was made based upon a combination of cardinal clinical symptoms (e.g. ascites and esophageal varices), laboratory findings (e.g. hypoalbuminemia, hyperbilirubinemia, abnormal coagulation profiles) and a preceding history of
Discussion
We revealed that the mean urinary 6β-HC/C ratio obtained from the patients with liver cirrhosis was significantly (P<0.05) lower than that obtained from healthy subjects (Fig. 1C). In addition, using the multiple regression analysis we demonstrated that only serum albumin concentrations would significantly (P<0.05) associated with the overall variability of 6β-HC/C ratios in the patients with chronic liver diseases and healthy subjects (Fig. 2). Because hypoalbuminemia in patients with liver
Acknowledgments
The authors thank S. Kurihara and N. Komada for their excellent technical assistance.
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