摘要:

At least three types of congenital nonhemolytic unconjugated hyperbilirubinemias, including the rare Crigler-Najjar (CN) diseases (Types I or II) and Gilbert's syndrome (affecting 6% of the population) are associated with either absent or reduced hepatic UDP-glucuronosyltransferase (transferase) activity towards the potentially toxic endogenous acceptor, bilirubin. Here, we review the biochemical studies associated with these deficiencies. Accumulated evidence from studies with an animal model of CN Type I syndrome, the Gunn strain of hyperbilirubinemic rats, suggested that multiple isozymes are absent. These confounding observations have been clarified by a flurry of reports which have revealed the molecular basis for the complex disease phenotype in the Gunn rat and by the isolation and description of a novel human gene complex,UGT1, which encodes multiple and independently-regulated transferase isozymes that contain identical carboxyl terminal regions (246 amino acids). Finally, we discuss the implications of the gene organization and genetic defects determined for four different CN Type I individuals as a basis for a model which explains the inheritance pattern and genotypes of other familial unconjugated hyperbilirubinemias.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We describe the isolation of the humanCYP2C18gene, a new member in the complexCYP2Csubfamily, associated with the genetically-determined polymorphism for (S)-mephenytoin hydroxylase. The 5‘ end ofCYP2C18gene was isolated from a human genomic library using a probe derived from theCYP2C10cDNA and the 5’ flanking region, exons 1 to 4 and intron-exon junctions were sequenced. With respect to intron-exon boundaries, the partial gene structure was identical to that of rat and rabbitCYP2Cgenes. Consensus sequences for putative ‘glucocorticoid responsive elements' were observed in the 5’ flanking region and in intron 1, an interesting feature in a so-called constitutively-expressed gene subfamily. The knowledge ofCYP2Cgene sequences is a prerequisite to genomic analysis by PCR techniques. Using oligonucleotides derived from the gene sequence, we were able to specifically detectCYP2C18mRNAs in human liver.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The wide variations in urinary bladder and colo-rectal cancer incidence in humans have been attributed in part to metabolic factors associated with exposure to carcinogenic aromatic and heterocyclic amines. Cytochrome P-4501A2 (CYP1A2), which catalysesN-oxidation, and acetyltransferase (NAT2) which catalysesN- andO-acetylation, both appear to be polymorphically distributed in human populations; and slow and rapid NAT2 phenotypes have been implicated as risk factors for these cancers. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. For the NAT2 phenotype, we confirm the valid use of the urinary molar ratio of AFMU/1-methylxanthine, even in alkaline urines. For the CYP1A2 phenotype, the urinary molar ratio of [1,7-dimethylxanthine+ 1,7-dimethyluric acid]/caffeine, taken at 4–5 h after caffeine ingestion, was identified from pharmacokinetic analyses of 12 subjects as being better correlated (r = 0.73;p= 0.007) with the rate constant for caffeine 3-demethylation than other previously suggested ratios. This procedure was then used to determine the CYP1A2 phenotype in subjects from Arkansas (n = 101), Italy (n =95), and China (n = 78). Statistical and probit analyses of nonsmokers indicated that the CYP1A2 activity was not normally distributed and appeared trimodal. This trimodality allowed arbitrary designation of slow, intermediate, and rapid phenotypes, which ranged from 12–13% slow, 51–67% intermediate, and 20–37% rapid, in the different populations. A reproducibility study of 13 subjects over a 5 day or 5 week period showed that, with one exception, intraindividual variability did not alter this CYP1A2 phenotypic classification. Induction of CYP1A2 by cigarette smoking was also confirmed by the increased caffeine metabolite ratios observed in the Arkansas and Italian smokers (blonde tobacco). However, Italian smokers of black tobacco and Chinese smokers did not appear to be induced. Furthermore, probit analyses of Arkansas and Italian blonde tobacco smokers could not discriminate between phenotypes, apparently as a consequence of enzyme induction.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used asin vivoprobes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone forN-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0–8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine theN-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p< 0.003). Analysis of Kaplan-Meier survival curves indicated that patients in the lowest tertile of debrisoquine hydroxylase activity were tumour-free for a longer time than those in the middle or upper tertiles of activity (p< 0.05) for both the whole group and the non-aggressive subgroup. Additionally, logistic regression analysis indicated a 6–7 fold relative risk for recurrence among patients with debrisoquine recovery ratios greater than 0.33 (p< 0.02). No differences in the mephenytoin R/S ratio, the dapsone recovery ratio, orN-acetylation phenotype were observed between patients who did or did not have a recurrence of their cancer, regardless of tumour histopathology. These observations are consistent with the hypothesis that debrisoquine 4-hydroxylase contributes to the activation of procarcinogens involved in tumour formation and recurrence, and suggest that assessment of P4502D6 activity may be useful as a prognostic indicator for bladder tumour recurrence following initial resection.

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:1992

数据来源: OVID