Polymorphic acetylation and aminopyrine demethylation in Gilbert's syndrome

Abstract

Polymorphic acetylation was investigated in twenty-seven patients with Gilbert's syndrome using the sulphadimidine test. Whereas the finding of 51% slow acetylators in seventy-eight control persons agreed well with the expected frequency in a continental European population, the prevalence of slow acetylators in Gilbert's syndrome was increased to 78% (P less than 0.03, Woolf's G-test). After oral administration of 14C-aminopyrine there was no significant difference between seventeen patients with Gilbert's syndrome and twenty-seven normal controls in total plasma clearance of aminopyrine (280 +/- SD 100 and 270 +/- 60 ml/min) and in the disappearance curve of 14CO2 in breath (0.23 +/- 0.04 and 0.22 +/- 0.03 h-1, respectively). Thus, whereas aminopyrine metabolism appears unaffected in the examined patients, the data documents a new association between slow acetylator status and Gilbert's syndrome.

N‐acetylation and debrisoquine hydroxylation polymorphisms in patients with Gilbert's syndrome.

“…Our results, with a greater number of patients, confirm the findings of Platzer et al (1978). 74.1% of the patients with Gilbert's syndrome were SA compared with 54.7% of the healthy volunteers.…”

“…A previous study suggested that the slow acetylator phenotype is more prevalent among individuals with Gilbert's syndrome (Platzer et al, 1978). These authors also reported lower plasma concentrations of AcSM at 6 h after SM administration and speculated on the absence of homozygous rapid genotypes in Gilbert's syndrome.…”

“…Furthermore, there is evidence that Gilbert's syndrome might be associated with other pharmacogenetic traits such as the acetylation polymorphism (Evans, 1989). In a group of 27 patients, the proportion of slow acetylators was found to be significantly higher than in controls (Platzer et al, 1978).…”

“…It has also been shown that the clearance of drugs which are metabolised by phase-I and conjugative reactions might be reduced (Ullrich et al, 1987). However, there are also reports that drug oxidation is unchanged (Ishizaki et al, 1984;Platzer et al, 1978). Furthermore, there is evidence that Gilbert's syndrome might be associated with other pharmacogenetic traits such as the acetylation polymorphism (Evans, 1989).…”

N-acetylation pharmacogenetics: a gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits.

“…In addition to increased adverse reactions in slow acetylators treated with drugs whose elimination is primarily determined by acetylation, there are a number of associations of the acetylator phenotype with drug-induced and spontaneous disease. However, apart from the increased incidence of bladder cancer in the slow-acetylator phenotype (7)-carcinogenic amines causing bladder cancer are substrates for NAT-the associations of polymorphic acetylation with Gilbert disease (8), advanced breast cancer (9), diabetes (10), and leprosy (11) remain mechanistically unexplained.…”