Relationship between graft cytochrome P-450 3A content and early morbidity after liver transplantation.
Cytochrome P-450 3A metabolizes CsA into several metabolites with very limited pharmacological activity and toxicity. In 40 liver donors, the relative concentrations of P-450 3A was assessed by immunoblot analysis using a specific monoclonal antibody exhibited a 10-fold variation (mean = 92 +/- 50 arbitrary units [AU]/mg) in levels. Problems consequent upon CsA usage (nephrotoxicity, neurotoxicity, and hypertension) occurred in 8 of 34 transplant recipients in the immediate postoperative period, and in these 8 patients the problems were always associated with low graft P-4503A levels (mean = 52 +/- 19 A.U./mg, P = 0.0003, cf. patients with no toxicity). Four of these patients had CsA levels that were also high, but 4 had CsA levels in the therapeutic range. Episodes of early graft rejection were related to higher P-450 3A levels (mean = 110 +/- 24 A.U./mg). Cytochrome P-450 3A levels were also found to be inversely related to CsA whole blood levels (assessed with a specific antibody 12 hr after the intravenous infusion of CsA at 1 mg/kg in the recipients (P < 0.02). Cytochrome P-450 3A can provide information that should allow individualized immunosuppression with CsA maintaining therapeutic levels but avoiding toxicity in susceptible individuals.
Lemoine
A
A
INSERM U75, CHU Necker Enfants-Malades, Université René Descartes, Paris, France.
Azoulay
D
D
Gries
J M
JM
Dennison
A
A
Castaing
D
D
Fredj
G
G
Debuire
B
B
Guengerich
F P
FP
Beaune
P
P
Bismuth
H
H
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine / Q000009:adverse effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology*; D016031:Liver Transplantation / Q000009:adverse effects* / Q000502:physiology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D013997:Time Factors; D014019:Tissue Donors
D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating