Gilbert's syndrome revisited.

Gilbert's syndrome, also known as benign hyperbilirubinaemia, was described more than 100 years ago. It has usually been considered a physiological abnormality characterised by a mild elevation of the systemic level of unconjugated bilirubin, in the absence of any underlying liver or overt haemolytic disease. However, since the re-discovery of the potent antioxidant effects of bilirubin in the late 1980s, as well as multiple intracellular signalling pathways affected by bilirubin, an ever-increasing body of evidence suggests that individuals with Gilbert's syndrome may benefit from the mild hyperbilirubinaemia and are actually protected from the development of a wide variety of "diseases of civilisation" such as cardiovascular diseases, certain cancers, and autoimmune or neurodegenerative diseases. This review analyses the current state of medical knowledge given recent discoveries in this rapidly developing field, as well as their possible clinical significance, and provides a new perspective on this condition.

A Gilbert syndrome-associated haplotype protects against fatty liver disease in humanized transgenic mice.

UDP-glucuronosyltransferases 1 A (UGT1A) enzymes are capable of detoxifying a broad range of endo- and xenobiotic compounds, which contributes to antioxidative effects, modulation of inflammation and cytoprotection. In the presence of low-function genetic UGT1A variants fibrosis development is increased in various diseases. This study aimed to examine the role of common UGT1A polymorphisms in NASH. Therefore, htgUGT1A-WT mice and htgUGT1A-SNP mice (carrying a common human haplotype present in 10% of the white population) were fed a high-fat Paigen diet for 24 weeks. Serum aminotransferase activities, hepatic triglycerides, fibrosis development and UGT1A expression were assessed. Microscopic examination revealed higher hepatic fat deposition and a significant induction of UGT1A gene expression in htgUGT1A-WT mice. In agreement with these observations, lower serum aminotransferase activities and lower expression levels of fibrosis-related genes were measured in htgUGT1A-SNP mice. This was accompanied by reduced PPARα protein levels in htgUGT1A-WT but not in SNP mice. Our data demonstrate a protective effect of a UGT1A SNP haplotype, leading to milder hepatic steatosis and NASH. Higher PPARα protein levels in animals with impaired UGT1A activity are the likely result of reduced glucuronidation of ligands involved in PPARα-mediated fatty acid oxidation and may lead to the observed protection in htgUGT1A-SNP mice.

[Role of bilirubin in the prevention of cardiovascular diseases and cancer]. / Úloha bilirubinu v prevenci kardiovaskulárních a nádorových onemocnení.

Oxidative stress contributes importantly to pathogenesis of numerous civilization diseases, including cardiovascular diseases, cancer, as well as autoimmune and neurodegenerative conditions. Bilirubin is the major product of the heme catabolic pathway in the intravascular compartment. For long time, bilirubin was considered to be only a waste product, however, recent data from the last two decades have proved its important protective properties, which contributes to defense against development of civilization diseases. Numerous experimental as well as clinical studies have demonstrated association between low bilirubin concentrations and cardiovascular diseases, as well as certain cancers. On the other hand, subjects with mildly elevated blood bilirubin levels, typical for Gilbert syndrome, have decreased risk of these diseases.

FEATURES OF GILBERT'S SYNDROME IN PATIENTS WITH DIFFERENT GENOTYPES UGT1AI.

The aim; to evaluate the clinical manifestations and data of instrumental methods in patients with Gilbert's syndrome and different genotype UGT1A1. MATERIALS AND METHODS: Clinical manifestations and results of instrumental methods were studies in 104 patients with Gilbert's syndrome (UGIlAl gene mutation rs8175347), including 75 with the homozygous variant (genotype 7TA*7TA) and 29 - with heterozygous variant (genotypes 6TA*7TA or 6TA*STA). RESULTS: The most frequent clinical manifestation was asthenovegetative syndrome. The promoter of the appearance/intensification ofjaundice were physical activity, stress and viral infections. Homozygotes exhibit an earlier manifestation of the disease, higher rates of bilirubin (sometimes not only due to deconjugating), a greater variety of stigmas undifferentiated dysplasia of connective tissue, more frequent detection of biliary sludge or gallstones. The clinical observation of a family case of Gilbert's syndrome where the mother is a homozygote, and the son - heterozygotes on UGT1A1 mutation is presented, which shows the above differences associated with genotype. CONCLUSION: Patients with asthenic constitution and the stigma dysplasia of connective tissue have to be examined by the presence of mutations rs8175347 gene UGT1A1. The carrier not only homozygous but with the heterozygous variant mutations may require changes in the interpretation of symptoms, lifestyle, medication, etc.

Perfluorocarbons and Gilbert syndrome (phenotype) in the C8 Health Study Population.

BACKGROUND: Gilbert syndrome (GS) is an inherited defect of bilirubin conjugation, most commonly caused by a gene mutation for the enzyme UGT1A. GS is known to affect the metabolism and excretion of drugs and xenobiotics. Perfluorocarbon compounds (PFCs) are bio-persistent environmental contaminants that affect metabolic regulation. In this study, we examined the associations of GS phenotype and serum PFCs in the C8 Health Study Population. MATERIALS AND METHODS: Using 2005-2006 data from a large PFC-exposure population survey, we compared serum PFCs concentrations between GS and non GS clinical phenotypes, in a cross sectional design, adjusting for standard risk factors, including age, BMI, smoking status, socioeconomic status and gender. RESULTS: Among 10 PFC compounds considered, only perfluorohexanoic acid (PFHxA) was seen at a significantly higher concentration in GS men and women. CONCLUSION: PFHxA exposure may be associated with GS. Our findings do not support increased exposure in GS for other PFCs.

Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences.

Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler-Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin-Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.

[Relationship of bilirubin to diseases caused by increased oxidative stress]. / Vztah bilirubinu k nemocem vyvolaným zvýseným oxidacním stresem.

Oxidative stress contributes importantly to pathogenesis of numerous civilization diseases, including cardiovascular diseases, cancer, as well as autoimmune and neurodegenerative conditions. Bilirubin is the major product of the heme catabolic pathway in the intravascular compartment. For long time, bilirubin was considered to be only a waste product, however, recent data from the last 2 decades have proved its important antioxidant properties, which contributes to defense against increased oxidative stress. Numerous experimental as well as clinical studies have demonstrated association between low bilirubin concentrations and cardiovascular diseases, diabetes, certain cancers, autoimunne diseases, such as lupus erythematodes, or rheumatoid arthritis or neurological psychiatric disorders, such as schizofrenia. On the other hand, subjects with mildly elevated blood bilirubin levels, typical for Gilbert syndrome, have decreased risk of these diseases.

Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome.

A protective association between bilirubin and atherosclerosis/ischemic heart disease clearly exists in vivo. However, the relationship between bilirubin and in vivo oxidative stress parameters in a clinical population remains poorly described. The aim of this study was to assess whether persons expressing Gilbert syndrome (GS; i.e., unconjugated hyperbilirubinemia) are protected from thiol oxidation and to determine if this, in addition to their improved lipoprotein profile, could explain reduced oxidized low-density lipoprotein (oxLDL) status in them. Forty-four matched GS and control subjects were recruited and blood was prepared for the analysis of lipid profile and multiple plasma antioxidants and measures of oxidative stress. GS subjects possessed elevated plasma reduced thiol (8.03±1.09 versus 6.75±1.39 nmol/mg protein; P<0.01) and glutathione concentrations (12.7±2.39 versus 9.44±2.45 µM; P<0.001). Oxidative stress status (reduced:oxidized glutathione; GSH:GSSG) was significantly improved in GS (0.49±0.16 versus 0.32±0.12; P<0.001). Protein carbonyl concentrations were negatively associated with bilirubin concentrations and were significantly lower in persons with >40 µM bilirubin versus controls (<17.1 µmol/L; P<0.05). Furthermore, absolute oxLDL concentrations were significantly lower in GS subjects (P<0.05). Forward stepwise regression analysis revealed that bilirubin was associated with increased GSH:GSSG ratio and reduced thiol concentrations, which, in addition to reduced circulating LDL, probably decreased oxLDL concentrations within the cohort. In addition, a marked reduction in total cholesterol concentrations in hyperbilirubinemic Gunn rats is presented (Gunn 0.57±0.09 versus control 1.69±0.40 mmol/L; P<0.001), arguing for a novel role for bilirubin in modulating lipid status in vivo. These findings implicate the physiological importance of bilirubin in protecting from atherosclerosis by reducing thiol and subsequent lipoprotein oxidation, in addition to reducing circulating LDL concentrations.

Gilbert syndrome: the UGT1A1*28 promoter polymorphism as a biomarker of multifactorial diseases and drug metabolism.

Gilbert syndrome belongs to the group of the most common human metabolic disorders and is characterized by an elevated level of bilirubin in blood serum. A polymorphism of the 5´ end of the UGT1A1 gene promoter, a homozygous insertion of TA pairs (genotype UGT1A1*28/*28), results in a decrease in bilirubin glucuronidation activity and therefore leads to an increase in the level of unconjugated bilirubin (hyperbilirubinemia). Genotyping the UGT1A1 promoter is an important step in the determination of the etiology of free hyperbilirubinemia of unknown origin. Molecular diagnosis enables avoiding invasive diagnostic procedures, such as liver biopsy, in establishing the appropriate diagnosis and prognosis, as well as in establishing the correct therapeutic procedures in a variety of diseases (e.g., chemotherapy or bone marrow transplantation). Moreover, the UGT1A1*28/*28 genotype has emerged as an important element in drug tolerance, as well as in multifactorial diseases, such as cancer. However, the role of this polymorphism is still not completely understood. In this review we have summarized current knowledge and attempted to propose directions for further research.

Is Gilbert syndrome a new risk factor for breast cancer?

Patients with Gilbert syndrome have an impaired function of the enzyme UGT1A1, responsible for the degradation of 4-OH-estrogens. These elements are produced by the degradation of estrogens and are well-known carcinogens. In theory, patients with Gilbert syndrome accumulate 4-OH-estrogens and, therefore, might have a higher risk for breast cancer, especially when exposed to higher levels of estrogens. If this theory is true, a new risk group for breast cancer would be described, producing new insights in breast carcinogenesis.

Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition.

BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0×10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1×10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.

Combined effect of regulatory polymorphisms on transcription of UGT1A1 as a cause of Gilbert syndrome.

BACKGROUND: Gilbert syndrome is caused by defects in bilirubin UDP-glucuronosyltransferase (UGT1A1). The most common variation believed to be involved is A(TA)7TAA. Although several polymorphisms have been found to link with A(TA)7TAA, the combined effect of regulatory polymorphisms in the development of Gilbert syndrome remains unclear. METHODS: In an analysis of 15 patients and 60 normal subjects, we detected 14 polymorphisms and nine haplotypes in the regulatory region. We classified the 4-kbp regulatory region of the patients into: the TATA box including A(TA)7TAA; a phenobarbital responsive enhancer module including c.-3275T>G; and a region including other ten linked polymorphisms. The effect on transcription of these polymorphisms was studied. RESULTS: All haplotypes with A(TA)7TAA had c.-3275T>G and additional polymorphisms. In an in-vitro expression study of the 4-kbp regulatory region, A(TA)7TAA alone did not significantly reduce transcription. In contrast, c.-3275T>G reduced transcription to 69% of that of wild type, and the linked polymorphisms reduced transcription to 88% of wild type. Transcription of the typical regulatory region of the patients was 56% of wild type. Co-expression of constitutive androstane receptor (CAR) increased the transcription of wild type by a factor of 4.3. Each polymorphism by itself did not reduce transcription to the level of the patients, however, even in the presence of CAR. CONCLUSIONS: These results imply that co-operation of A(TA)7TAA, c.-3275T>G and the linked polymorphisms is necessary in causing Gilbert syndrome.

Bone mineral densities in individuals with Gilbert's syndrome: a cross-sectional, case-control pilot study.

BACKGROUND: Unconjugated bilirubin inhibits osteoblastic proliferative activity in vitro, raising the possibility that Gilbert's syndrome (GS) patients are at increased risk of osteoporosis. OBJECTIVES: To compare bone mineral density (BMD), serum parathyroid hormone (PTH), C-telopeptide (CTX) and osteocalcin levels in GS subjects versus matched controls in a cross-sectional, case-control study. METHODS: BMD determinations were obtained with central dual energy x-ray absorptiometry. Serum PTH, CTX and osteocalcin levels were measured by enzyme immunoassay. RESULTS: A total of 17 GS and 30 control subjects were studied. Overall, there were no significant differences in BMD, PTH, CTX or osteocalcin levels between the two groups. However, when older (older than 40 years of age) and younger (40 years of age and younger) cohorts were considered separately, the older GS cohort had significantly decreased total hip BMD, T scores and Z scores, and femoral neck BMD, T scores and Z scores (P<0.005 for each parameter, respectively) compared with older control subjects. Serum osteocalcin levels were lower in the older versus younger GS cohort (P=0.006). An inverse correlation existed between all subjects' serum unconjugated bilirubin levels and total body BMD determinations (r=-0.42; P=0.04). On univariate analysis, the association between serum unconjugated bilirubin and total body BMD was not significant (P=0.066), nor was serum unconjugated bilirubin identified as a risk factor for low BMD when entered into multivariate analyses. CONCLUSIONS: The results of the present pilot study warrant further research involving larger numbers of subjects and longitudinal measurements to determine whether GS is associated with decreased BMD, particularly in older GS subjects.

Pharmacogenetics of Gilbert's syndrome.

Gilbert's syndrome is characterized by mild unconjugated nonhemolytic hyperbilirubinemia, which does not lead to hepatic inflammation, fibrosis, chronic liver disease or liver failure. Almost 100 years after its clinical description, it was linked to a genetic variant of the human bilirubin UDP-glucuronosyltransferase (UGT1A1), UGT1A1 (*)28, found in approximately 40% of Caucasoid individuals. Over 113 UGT1A1 variants have since been reported, leading to a continuous spectrum from mild hyperbilirubinemia to life-threatening jaundice. UGT1A variants are evolutionary diverse and occur in the context of haplotypes combining different variants within the promoter, the 5 exons, as well as introns of the UGT1A1 gene, and also in combination with other UGT1A genes expressed in the liver and the extrahepatic gastrointestinal tract. The variation of glucuronidation hidden behind Gilbert's syndrome impacts drug therapy, which includes the well-characterized examples of irinotecan and atazanavir. The prediction of unwanted drug reactions associated with Gilbert's syndrome will improve drug safety, therapeutic individualization and impact the drug-development process.

Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter.

OBJECTIVES: Gilbert's syndrome is a congenital, nonhemolytic, unconjugated hyperbilirubinemia. The most common genotype of Gilbert's syndrome is the homozygous polymorphism, A(TA)7TAA, in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), with a thymine adenine insertion in the TATA-box-like sequence, which results in a decrease in UGT1A1 activity. The mechanism responsible for this decrease in UGT1A1 activity, however, has not been elucidated. To clarify the mechanism underlying this deficiency in UGT1A1 activity in patients with Gilbert's syndrome. METHODS: The promoter activity assay using the wild-type A(TA)6TAA or the mutant A(TA)7TAA promoter and a luciferase reporter was performed in two different hepatoma cell lines. The binding affinity for a nuclear protein complex or for TATA-binding protein was evaluated by a competitive electophoretic mobility shift assay using wild-type or mutant TATA-box-like oligonucleotide probes and nuclear extract or TATA-binding protein. The formation of complexes between TATA-binding protein and wild-type or mutant oligonucleotide probes was also studied by a quantitive electophoretic mobility shift assay. RESULTS: A TA insertion in the TATA-box-like sequence of the promoter activity of UGT1A1 gene. A competitive electrophoretic mobility shift assay showed a decrease in nuclear protein complex binding affinity and TATA-binding protein binding affinity of the mutant TATA-box-like sequence A(TA)7TAA. When the mutants A(TA)5TAA and A(TA)8TAA were also compared, quantitative electrophoretic mobility shift assay demonstrated that the TATA-binding protein binding affinity progressively decreased as the number of TA repeats in the TATA-box-like sequence increased. CONCLUSION: TA insertion in the TATA-box-like sequence of the UGT1A1 promoter affected its binding affinity for TATA-binding protein, causing a decrease in its activity. This explains the pathogenesis of Gilbert's syndrome.

Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases.

Human gene families encoding UDP-Glucuronosyltransferases (UGTs) have been identified and partially characterised. This family of enzymes catalysed the glucuronidation of drugs, xenobiotics and endobiotics. Genetic mutations and polymorphisms have been identified in several UGT genes and examples should be anticipated in all UGT genes. A common genetic defect in the TATA box promoter of the UGT1A1 gene is associated with Gilbert's Syndrome (GS) causing mild hyperbilirubinaemia. Recently, adverse effects of anticancer agents have been observed in Gilbert's patients due to reduced drug or bilirubin glucuronidation.

Heterogeneity of paracetamol metabolism in Gilbert's syndrome.

Gilbert's syndrome (GS) is an inherited bilirubin UDP-glucuronosyl transferase deficiency. The object of this study was to investigate the possible effects of this disorder on the metabolism of a drug, such as paracetamol, which is basically eliminated by hepatic glucuronidation. We studied 32 healthy volunteers and 18 people with GS, all of whom were given 1.5 g of paracetamol orally. In the 24 h urine collected, we determined the elimination of free paracetamol, the conjugates (glucuronide, sulphate) and the oxidation products (cysteine, mercapturic acid) by high pressure liquid chromatography (HPLC). The results are given as a percentage of the total quantity of paracetamol eliminated. The patients with GS were divided into 2 subgroups (GS-I and GS-II) according to whether glucuronidation was more or less than 50%. The overall results of the GS group showed no significant difference in the urinary elimination of metabolites as compared to the control group. However, in subgroup GS-I, a reduction in glucuronidation (P = 0.0012) and an increase in oxidation (P = 0.0051) was seen, as compared with the other 2 groups. There was inverse correlation between the glucuronide produced by conjugation and the oxidation products (r = -0.8718; P<0.005). People with GS are a heterogeneous group with respect to the metabolism of paracetamol. In one subgroup this was normal. In the other subgroup there was a marked reduction in glucuronidation and an increase in oxidation. These changes could mean that people in this subgroup are more liable to liver damage after an overdose of paracetamol.

Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.

BACKGROUND: CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly eliminated through conjugation by hepatic uridine diphosphate glucuronosyl transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation. Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may have an increased risk for related CPT-11 toxicity. PATIENTS AND METHODS: Two patients with metastatic colon cancer and Gilbert's syndrome were treated with CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC. RESULTS: Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in every treatment cycle. Biliary index (after Gupta et al) values were well above 4000. CONCLUSION: We present the first clinical evidence linking bilirubin glucuronidation status and CPT-11 related toxicity. The severe toxicity experienced by the two patients with Gilbert's syndrome treated with CPT-11 based chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be predictive parameter of CPT-11 toxicity.

Sulfur amino acid metabolism in hepatobiliary disorders.

Sulfur amino acid metabolism was studied in patients with mild to severe forms of liver dysfunction and compared with that of healthy controls. Patients with mild liver dysfunction (for example, Gilbert's syndrome) had a normal sulfur amino acid metabolism. With increased inflammatory activity and cirrhosis (for example, chronic active hepatitis, alcohol-induced cirrhosis, and hepatic coma) a decreased ability to metabolize methionine (to cysteine, with cystathionine accumulation) and cysteine (to inorganic sulfate, with thiosulfate and N-acetylcysteine accumulation) was found. In contrast, transaminative metabolism of sulfur amino acids was preserved in patients with advanced forms of liver dysfunction, suggesting that transamination of sulfur amino acids is performed not only in the liver but also in extrahepatic tissues. Some implications of these findings are discussed.

Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome.

Gilbert's syndrome occurs in 5%-7% of the human population and is caused by an inherited deficiency in the glucuronidation of endogenous bilirubin, resulting in its accumulation and jaundice. The authors of the present study have previously shown that rats with a similar deficiency in bilirubin glucuronidation (Gunn rats) had reduced glucuronidation and enhanced susceptibility to the toxicity of the widely used analgesic, acetaminophen. Acetaminophen is eliminated primarily by glucuronidation, which prevents its cytochrome P-450-catalysed bioactivation to a hepatotoxic reactive intermediate. The purpose of this study was to determine whether people with Gilbert's syndrome had reduced glucuronidation and enhanced bioactivation of acetaminophen. Therefore, the biotransformation of acetaminophen, 20 mg/kg IV, was investigated in six subjects with Gilbert's syndrome (total bilirubin, 41 +/- 6 mumol/L; mean +/- SE) and six normal controls (total bilirubin, 11 +/- 2 mumol/L; P less than 0.01). Formation of the acetaminophen glucuronide conjugate measured by high-performance liquid chromatography was quantified by the ratio of the area under the plasma concentration-time curve (AUC) from 0 to 2 hours for the acetaminophen glucuronide divided by the AUC for acetaminophen. Acetaminophen bioactivation was quantified by the molar percentage of acetaminophen excreted in the urine during 24 hours as glutathione-derived conjugates (cysteine and mercapturic acid). Acetaminophen glucuronide formation in subjects with Gilbert's syndrome was 31% lower than that in normal controls (0.27 +/- 0.05 vs. 0.39 +/- 0.03; P less than 0.05), and bioactivation was 1.7-fold higher (3.5% +/- 0.4% vs. 2.1% +/- 0.3%; P less than 0.05). One control subject with normal bilirubin glucuronidation had substantially decreased acetaminophen glucuronide formation (0.20) and enhanced bioactivation (4.8%). Among all subjects, glucuronidation correlated inversely with bioactivation (r = -0.84; P less than 0.001), indicating that a decrease in a major pathway of elimination can shunt more drug through the toxifying route. Thus, a deficiency in bilirubin UDP-glucuronosyltransferase, evidenced by jaundice, can be paralleled by a deficiency in glucuronidation of other compounds. In these cases, jaundice can be a phenotypic determinant of enhanced acetaminophen bioactivation. On the other hand, some people with normal bilirubin glucuronidation may have a deficiency in the glucuronidation of acetaminophen; these people are not easily recognized.(ABSTRACT TRUNCATED AT 400 WORDS)