Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation*

Abstract

Objective-To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation.Methods-Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods.Results-The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean ± SD, 6.4 ± 5.1) was significantly higher than that after 1 month after surgery (2.1 ± 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 ± 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 ± 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 ± 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 ± 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups.Conclusions-We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after sugery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.Alterations in drug absorption, distribution, metabolism, and urinary and biliary excretion have been documented at various times after organ transplantation. 1 Drug metabolism in liver transplant patients is of particular concern because the liver is primarily responsible for the biotransformation of most xenobiotics. The procedure of transplanting a complete or partial liver from a donor to the recipient involves a number of steps that ultimately affect drug metabolism. The process of preservation, reperfusion injury, inflammatory changes associated with the surgical procedure, technical complications involving the flow of blood and bile, and the immunologic response of the recipient all produce complex effects that primarily ...

THECYP2E1-HUMANIZED TRANSGENIC MOUSE: ROLE OF CYP2E1 IN ACETAMINOPHEN HEPATOTOXICITY

“…Chlorzoxazone 6-hydroxylation has been commonly used to measure human CYP2E1 activity (Lucas et al, 1996(Lucas et al, , 1999Haufroid et al, 2002). Measurement of chlorzoxazone and trimethadione metabolism by CYP2E1 has also been used as an indicator for liver diseases in vivo and in vitro (Dilger et al, 1997;Burckart et al, 1998;Mishin et al, 1998;Dupont et al, 2000). An alternative method for measuring CYP2E1 activity has been to analyze p-nitrophenol hydroxylation ( p-nitrocatechol formation) (Zerilli et al, 1997).…”

Hepatic Cytochrome P450 2E1 Activity in Nondiabetic Patients With Nonalcoholic Steatohepatitis

“…CHZ, a centrally acting muscle relaxant, is primarily hydroxylated by CYP2E1 to 6-hydroxy CHZ and therefore has been extensively used as a selective probe for measuring hepatic CYP2E1 activity in humans. [17][18][19][20][21] Subjects were asked to avoid certain foods (grapefruit, vegetables from the mustard green family, and beverages containing xanthine and alcohol) for at least 72 hours, and, when possible, nonessential medications were discontinued one week before this test to reduce the chances of drug interference. Blood and urine samples were collected for 8 hours after administering a 500-mg dose of chlorzoxazone orally, followed immediately by 240 mL of water.…”

Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma

“…Over the decade, measurement of the metabolic rate of chlorzoxazone and trimethadione by CYP2E1 was used as an indicator for liver diseases in vivo and in vitro. [2][3][4][5] As CYP2E1 is an ethanol inducible enzyme, its functional characterization has been focused on alcoholic liver diseases; 6 therefore our knowledge of CYP2E1 in carcinogenesis is limited. Until recently, an in vitro study has revealed that overexpression of CYP2E1 induces cytotoxicity in human hepatoblastoma cell line (HepG2), 7 which suggested that expression of CYP2E1 may play a role in tumor cell proliferation.…”