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)