6-beta-hydroxycortisol and Liver-Cirrhosis

Topics: Adrenal Cortex; Adult; Amniotic Fluid; Animals; Arthritis, Rheumatoid; Cushing Syndrome; Depression; Female; Humans; Hydrocephalus; Hydrocortisone; Hydroxylation; Infant, Newborn; Infant, Premature; Liver Cirrhosis; Male; Meningomyelocele; Methods; Neoplasms; Pregnancy; Pregnancy Complications; Steroid Hydroxylases; Thyroid Diseases; Tissue Distribution

To study whether chronic liver disease (CLD) and genetic polymorphism affect the hepatic activity of cytochrome P450 (CYP) isoforms, we compared in vivo CYP2C19 and CYP3A activities using 3-hour omeprazole hydroxylation index (plasma concentration ratio of omeprazole to its 5-hydroxylated metabolite; a higher index indicates lower CYP2C19 activity) and partial formation clearance of cortisol to 6beta-hydroxycortisol (CL(cortisol-->6beta-HC)) in 31 CLD patients (9 with chronic hepatitis; 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, and 1 type C) and 30 healthy subjects with different CYP2C19 genotypes. The mean (+/-SEM) omeprazole hydroxylation index in CLD patients with homozygous extensive metabolizer (EM) genotype (*1/*1, n = 8), heterozyous EM (*1/*2, n = 11; *1/*3, n = 6) genotypes and poor metabolizer (PM) genotypes (*2/*2, n = 3; *3/*3, n = 3) were 17.15 +/- 2.12, 20.02 +/- 2.63, and 26.04 +/- 3.15, respectively, which were significantly higher compared with control subjects with the corresponding CYP2C19 genotypes (0.81 +/- 0.09, 1.55 +/- 0.20, and 15.5 +/- 1.52). CLD patients with PM genotype had significantly (P < .05) higher omeprazole hydroxylation indexes than did those with homozygous EM genotype, and those with heterozygous EM genotypes had intermediate values. The mean CL(cortisol-->6beta-HC) decreased significantly (P < .001) in CLD patients compared with control subjects (1.19 +/- 0.12 versus 2.26 +/- 0.24 mL/min). Multiple regression analysis showed that CLD, serum albumin level, and CYP2C19 genotype correlated significantly (P < .05) with the omeprazole hydroxylation index, whereas no significant correlation was observed between CL(cortisol-->6beta-HC) and other variables, except CLD. Because CLD and genetic polymorphism of CYP2C19 act additively to reduce CYP2C19 activity, genotyping these patients may be of value in averting adverse reactions of drugs that depend on CYP2C19 for elimination.

Topics: Adult; Aged; Aged, 80 and over; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Enzyme Inhibitors; Female; Genotype; Hepatitis C, Chronic; Humans; Hydrocortisone; Liver Cirrhosis; Male; Middle Aged; Mixed Function Oxygenases; Omeprazole; Polymorphism, Genetic

Poisoning can occur with chronic accumulation of a drug due to reduced metabolic capacity; conversely, under-treatment may occur due to an increased metabolic rate. Over half of all drugs are metabolized by the cytochrome P450 3A complex (CYP3A). The activity of CYP3A can be assessed by the urinary ratio of 6β-hydroxycortisol to cortisol. The aim of this study was to determine the usefulness of this ratio as a postmortem marker for determining whether altered CYP3A enzyme activity occurred prior to death. In a series of 244 postmortem cases, this ratio ranged from 0.014 to 78.6 (median 3.50). The median was significantly higher (5.14) in a subgroup of 28 cases that exhibited the presence of CYP3A-inducing drugs. In cirrhosis, the median ratio was 1.69. This pointed to a reduced metabolic capacity of CYP3A. Thus, the ratio may constitute a rough indicator of the CYP3A metabolic capacity, which could be of value in special cases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Carbamazepine; Child; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Female; Forensic Toxicology; Humans; Hydrocortisone; Liver Cirrhosis; Male; Middle Aged; Oxcarbazepine; Phenobarbital; Phenytoin; Young Adult

Topics: Humans; Hydrocortisone; Lipid Metabolism; Liver Cirrhosis