CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients.

Abstract

1. The in vitro hepatic metabolism of lignocaine to monoethylglycinexylide (MEGX) is mediated by CYP3A4 and that of coumarin to 7‐hydroxycoumarin (7OHC) by CYP2A6. We investigated the usefulness of monitoring serum MEGX concentrations (after 1 mg kg‐1 lignocaine i.v.) and urinary 7OHC excretion (after 5 mg coumarin p.o.) to reflect liver function in patients with liver (n = 36), kidney (n = 12) and epileptic (n = 12) disease and in control subjects (n = 20). The extent of liver disease was assessed using measurements of serum aminoterminal propeptide (PIIINP) and Child‐Pugh grades. 2. Serum concentrations of MEGX were decreased in severe (4.6 +/‐ 3.0 s.d. ng ml‐ 1), moderate (19.1 +/‐ 11.6 s.d. ng ml‐1) and mild (32.8 +/‐ 14.2 s.d ng ml‐1) liver disease as compared with controls (53.4 +/‐ 15.8 s.d ng ml‐1). The excretion of 7OHC over 2 h was decreased in severe (18.0 +/‐ 10.3 s.d % of dose) and moderate (34.2 +/‐ 15.6 s.d %), but not in mild (49.7 +/‐ 19.0 s.d %) liver disease as compared with that in controls (56.2 +/‐ 11.6%). 3. In epileptic patients the urinary recovery of 7OHC was increased (2 h value 69.5 +/‐ 13.2 s.d %) suggesting enzyme induction. In contrast, serum MEGX concentration were low (40.0 +/‐ 14.1 s.d ng ml‐1), possibly due to competition for CYP3A4 between lignocaine and antiepileptic drugs. 4. In patients with kidney disease serum MEGX concentration (56.5 +/‐ 26.1 s.d ng ml‐1) was similar to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism and Disposition Kinetics of Nicotine

“…Total clearance was lower by 23% and renal clearance lower by 49% in the elderly compared with young adults. Lower CYP2A6-mediated metabolism in older subjects has also been demonstrated with coumarin (Sotaniemi et al, 1996). Lower nicotine metabolism in the elderly may be contributed to by reduced liver blood flow, as no decrease in CYP2A6 protein levels or nicotine metabolism in liver microsomes due to age has been detected (Shimada et al, 1994;Messina et al, 1997;Baker et al, 2001).…”

“…Hepatitis A markedly reduces coumarin metabolism in adults and children (Pasanen et al, 1997), whereas liver fluke parasite infection induces coumarin metabolism (Satarug et al, 1996). Acute alcohol ingestion is without effect on coumarin metabolism , whereas patients with alcoholic liver disease have reduced metabolism of coumarin detected both in liver biopsy samples and in vivo (Kratz, 1976;Pelkonen et al, 1985;Sotaniemi et al, 1995). Although the total metabolism by CYP2A6 is reduced in patients with alcoholic liver disease and viral hepatitis, CYP2A6 expression seems to be induced in areas of the liver immediately next to fibrotic and inflamed areas as shown with in situ hybridization and immunohistochemistry (Palmer et al, 1992;Kirby et al, 1996;Niemela et al, 2000).…”

“…A tendency for higher metabolism in women compared with men has been detected in most (six of seven studies) of the phenotyping studies using coumarin 7-hydroxylation or conversion of caffeine metabolite 1,7-dimethylxanthine to 1,7-dimethyluric acid as a measure of CYP2A6 activity (Rautio et al, 1992;Iscan et al, 1994;Sotaniemi et al, 1996;Krul and Hageman, 1998;Nowell et al, 2002;Ujjin et al, 2002;Xu et al, 2002c). Two of these studies showed a statistically significant 98 difference; 17% higher 3-h urinary excretion of 7-hydroxycoumarin in females compared with males was reported by Ujjin et al (2002), and the study by Iscan et al (1994) showed 11% higher 7-hydroxycoumarin excretion in women compared with men in a 2-h coumarin test.…”

Transcriptional Regulation of the Human CYP2A6 Gene

“…Indeed, more than a 100-fold variability in both CYP2A6 mRNA and protein levels has been reported (Yun et al, 1991;Shimada et al, 1994;Pelkonen et al, 2000;Rodriguez-Antona et al, 2001). Although part of these interindividual differences in CYP2A6 activity might be attributed to physiological factors (Ujjin et al, 2002), disease (Pasanen et al, 1997;Raunio et al, 1998), and exposure to clinically used drugs (Dalet-Beluche et al, 1992;Sotaniemi et al, 1995;Donato et al, 2000), a major part of the interin-dividual and interethnic variability, at least in Asians, is determined by already described genetic polymorphisms in the CYP2A6 gene (CYP2A6*4; frequency 1 and 15-20% in Europeans and Asians, respectively. CYP2A6*2; frequency 1-3 and 0% in Europeans and Asians, respectively) (Oscarson, 2001;Tyndale and Sellers, 2002).…”

Dexamethasone-Mediated Up-Regulation of HumanCYP2A6Involves the Glucocorticoid Receptor and Increased Binding of Hepatic Nuclear Factor 4α to the Proximal Promoter

“…Twenty-six allelic variants of CYP2A6 have been identified to date, resulting in altered enzyme activity that affects the metabolism of substrates ranging from pharmaceuticals to toxins including procarcinogens (Raunio et al, 2001). Although interindividual variation in CYP2A6 levels has been attributed to physiological factors (Ujjin et al, 2002), inflammatory disease (Kirby et al, 1996), pharmaceutical exposure (Sotaniemi et al, 1995;Pelkonen et al, 2000), and genetic polymorphisms within the CYP2A6 coding region (Raunio et al, 2001), little is known about CYP2A6 transcriptional regulation and its involvement in the observed variation in expression.…”