Hepatitis A impairs the function of human hepatic CYP2A6 in vivo

Abstract

Hepatitis virus A (HVA) is a worldwide sporadic disease but its effects on pharmacokinetics and individual drug responses have not been studied. In this study, the 7-hydroxycoumarin (7OHC) excretion test used in vivo as a bioindex of hepatic CYP2A6 activity was performed in 20, previously healthy, acute jaundice HVA patients. Volunteers with an acute HVA were treated with one p.o. administration of 5 mg coumarin (Venalot®). Among the patients, 11 were children (6–10 years; two girls and nine boys), the rest (15–40 years old) consisted of two men and seven women. Urinary excretion of 7OHC was measured after overnight fasting in four fractions: 0 h before any medication (to detect if any basal 7OHC excretion exits), and after a 5-mg coumarin capsule p.o., 0–2, 2–4 and 4–8 h fractions were collected and urine volumes were recorded. Urinary excretion of 7-hydroxycoumarin occurred to a similar extent in healthy adults and children. The first 2-h 7OHC excretion was decreased by 26% (P<0.05) and total (0–8 h) 7OHC excretion was decreased by 37% (P<0.01) among HVA-positive adults (age range 15–40 years) compared with the values obtained from healthy volunteers. In 11 HVA-positive children (age 6–10 years), the first 2-h 7OHC excretion was only 20% (P<0.0001) and the total 7OHC excretion 28% (P<0.0001) of the value observed in healthy controls. These results suggest that (i) an acute HVA decreases the metabolic clearance of drugs such as coumarin which are rapidly metabolised by CYP2A6 and (ii) this decrease is even more prominent in children. Such metabolic responses may be of clinical importance and may also interfere with other drug therapy in these patients.

Introduction

Hepatitis A (HVA) is a worldwide sporadic disease that is commonly transmitted by faecal contaminated food or water. Viraemia lasts for several weeks but never becomes chronic. Therefore, the therapy is mainly palliative, often consisting of supportive nutrition with vitamins. HVA is usually mild in children but in neonates HVA may persist for up to 6 months. The disease is more serious and prolonged in adults and the patients may receive spasmolytic, analgesic, antiemetic or sedative drug therapy. When the HVA is severe, the patients are jaundiced and serum transaminases are clearly elevated. In countries with high standards of living, HVA is an increasingly common problem in drug abusers and homosexuals, and in certain problem social cases in very young children, most probably due to poor sanitation. HVA-induced hepatic pathogenesis is well known (Sherlock, 1985) but its effects on pharmacokinetics and individual drug responses have not been studied. This is the first study to demonstrate that acute HVA infection affects human drug metabolism in vivo.

The expression of xenobiotic metabolising enzymes can be affected by chemical inducers, nutritional conditions, growth factors and inflammation mediators (Renton and Knickle, 1990, Wong et al., 1993, Kirby et al., 1994). Moreover, several liver diseases interfere with the hepatic clearance of drugs. For instance, a severe, moderate or even mild alcoholic liver disease decreases CYP3A4-dependent metabolism of lignocaine to monoethylglycinexylide (Sotaniemi et al., 1995) and acute hepatitis B infection slightly decreases the metabolic clearance of antipyrine in vivo (Farrell et al., 1978). Interestingly, hepatotoxic agents have been shown to increase the xenobiotic metabolising enzymatic activities in vitro in response to the overt liver damage (Pellinen et al., 1993).

Coumarin (1,2-benzopyrone), possesses anti-inflammatory, smooth muscle relaxing and the sphincter of Oddi relaxing properties, thus improving drainage of the bile, and can be used for oedema and hepatitis therapy (Casley-Smith and Casley-Smith, 1986). Coumarin is prominently 7-hydroxylated to 7-hydroxycoumarin (7OHC) by a specific cytochrome P-450 enzyme CYP2A6 in man. More than 95% of the 7OHC formed is excreted in 4 h as the glucuronide conjugate in urine with large interindividual variation (Cohen, 1979, Yamano et al., 1990, Rautio et al., 1992). No significant differences in 7OHC secretion between the sexes have been found (Rautio et al., 1992) but homozygous for the mutant CYP2A6v1 variant allele are deficient in their ability to produce 7OHC (Fernandez-Salguero et al., 1995). The coumarin excretion test, since it is a noninvasive test and easy to adapt for a clinical study, measures directly the metabolic capacity of CYP2A6 in man in vivo.

In this study, we examined the effect of acute HVA infection in children and adults on the expression of human hepatic CYP2A6 using urinary excretion of 7OHC as an activity marker.