FK 506 renal toxicity and lack of detectable cytochrome P-450 3A in the liver graft of a patient undergoing liver transplantation

Abstract

Many commonly used drugs are substrates for hepatic cytochrome P-450 3A in human beings, and its role in the metabolism of potentially toxic immunosuppressants has been highlighted (cyclosporine, FK 506). One hundred fifty human liver grafts were biopsied before and after liver transplantation, and levels of cytochromes P-450 3A, 1A2, 2D6 and 2C were estimated by means of the Western-blot technique and correlated with histological appearance, glycogen content and clinical course. In 15 of the grafts, cyclosporine oxidase was also measured, and in 12 of 15 recipients, urinary 6 beta-hydroxycortisol excretion was assayed. A wide range of cytochrome P-450 3A values were observed (25 to 366 arbitrary units/mg; mean, 105 +/- 63 arbitrary units/mg). In one graft (no. 730) no cytochrome P-450 3A was detectable on immunoblotting, despite increasing homogenate concentrations. In this sample, cytochromes P-450 1A2, 2D6, and 2C were present in normal ranges. Levels of cyclosporine 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 administration protocol and drug plasma level in the normal range. The subsequent appearance of the cytochrome P-450 3A was associated with the consequent tolerance of oral FK 506. The absence of detectable amounts of P-450 3A in one biopsy from a donated human liver graft dramatically emphasizes the extreme range of this enzyme levels and has important clinical implications.