Relationship between the severity of alcoholic liver cirrhosis and the metabolism of caffeine in 226 patients.
OBJECTIVE
To evaluate the polygenic regulated caffeine metabolism in a group of 226 patients with liver alcoholic cirrhosis classified according to the Child score.


METHODS
Over a 14-year period an hepatic function test, using caffeine as probe drug, has been systematically associated to the usual clinical and biochemical investigations performed in patients with liver alcoholic cirrhosis. "Caffeine test" consisted in a 200 mg caffeine oral intake. Urines were collected over 24 hours: caffeine (137X), 1-7 dimethylxanthine (17X), 1-3 dimethylxanthine (13X), 1-3 dimethylurate (13U), 3-7 dimethylxanthine (37X), 1-7 dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), 7-methylxanthine (7X), 3-methylxanthine (3X), and 5-acetylamino-6-formylamino-3-methyluracyl (AFMU) were analyzed by high performance liquid chromatography (HPLC). Total and individual metabolite urinary elimination rates were expressed in micromol/24 hours. Enzyme activities were evaluated from the following urinary metabolites ratios: (AFMU+1U+1X)/17U for CYPIA2, 17U/17X for CYP2A6, AFMU/(AFMU+ 1U+1X) for NAT-2, 1U/1X for XO.


RESULTS
Compared to healthy subjects, whatever the Child score, caffeine metabolism was reduced by half in patients with alcoholic cirrhosis. The main cause was the decreased CYP1A2 activity. On the other hand, XO and CYP2A6 activities were increased and NAT-2 activity remained unchanged in slow acetylators (SA) and decreased in rapid acetylators (RA) Child B and C. Bimodality of NAT-2 distribution was unclear, but a right assignment of RA and SA phenotype in cirrhotic patients, confirmed by comparison with genotype, was obtained, using the antimode value of NAT-2 distribution used in healthy subjects. At last, there was an interindividual variability in caffeine metabolism as great as in the usual laboratory parameters.


CONCLUSIONS
Metabolism of caffeine is decreased in patients with alcoholic liver cirrhosis. This decrease paralleled the modifications of the usual laboratory tests and does not bring additional information on the severity of the disease. But the equilibrium between the various metabolic pathways of caffeine is impaired. Beyond the changes of a specific enzymatic activity, this must be taken into account particularly for drugs whose metabolism is of the polygenic regulation type.
Bechtel
Y C
YC
Pharmacologie Clinique, Faculté de Médecine et de Pharmacie, Hôpital Universitaire, Besançon, France.
Haffen
E
E
Lelouët
H
H
Brientini
M P
MP
Paintaud
G
G
Miguet
J P
JP
Bechtel
P R
PR
D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002110:Caffeine / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000378:metabolism* / Q000652:urine; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000503:physiopathology*; D006899:Mixed Function Oxygenases / Q000378:metabolism
D000697:Central Nervous System Stimulants; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D001191:Arylamine N-Acetyltransferase