FK-506 RENAL TOXICITY AND LACK OF DETECTABLE CYTOCHROME-P-450 3A IN THE LIVER GRAFT OF A PATIENT UNDERGOING LIVER-TRANSPLANTATION

Many commonly used drugs are substrates for hepatic cytochrome P-450 3 A in human beings, and its role in the metabolism of potentially toxic immunosuppressants has been highlighted (cyclosporine, FK 506). One h undred fifty human liver grafts were biopsied before and after liver t ransplantation, and levels of cytochromes P-450 3A, 1A2, 2D6 and 2C we re estimated by means of the Western-blot technique and correlated wit h histological appearance, glycogen content and clinical course. In 15 of the grafts, cyclosporine oxidase was also measured, and in 12 of 1 5 recipients, urinary 6 beta-hydroxycortisol excretion was assayed. A wide range of cytochrome P-450 3A values were observed (25 to 366 arbi trary units/mg; mean, 105 +/- 63 arbitrary units/mg). In one graft (no . 730) no cytochrome P-450 3A was detectable on immunoblotting, despit e increasing homogenate concentrations. In this sample, cytochromes P- 450 1A2, 2D6, and 2C were present in normal ranges. Levels of cyclospo rine oxidase and 6 beta-hydroxycortisol in the urine specimens of the recipient were found to be low. The recipient of graft 730 experienced reversible complications of FK 506 therapy despite adherence to the a dministration protocol and drug plasma level in the normal range. The subsequent appearance of the cytochrome P-450 3A was associated with t he consequent tolerance of oral FK 506. The absence of detectable amou nts of P-450 3A in one biopsy from a donated human liver graft dramati cally emphasizes the extreme range of this enzyme levels and has impor tant clinical implications.