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S M de Morais

Publications and source records attributed to S M de Morais.

16 recordsLinked to original sources
PubMed2004

Effects of essential oil of Alpinia zerumbet on the compound action potential of the rat sciatic nerve.

Alpinia zerumbet, known popularly as "colônia" in Northeastern Brazil, is a medicinal plant that has been used widely in folk medicine as teas and infusions for the treatment of intestinal and cardiovascular diseases, including arterial hypertension. Our previous studies have demonstrated that the essential oil of A. zerumbet (OEAZ) is very active on excitable tissues, such as smooth muscle, and in this study we verified its effects on the compound action potential (CAP) of rat sciatic nerve. EOAZ induced a dose-dependent blockade of the CAP. Control peak-to-peak amplitude and conduction velocity of CAPs were 7.6 +/- 0.43 mV and 80.6 +/- 3.19 m/s, respectively. At 60 microg/ml, EOAZ induced no demonstrable effect. Conduction velocity was significantly reduced at 180 min of preparation exposure to 100 microg/ml of EOAZ. At 300, 600 and 2000 microg/ml doses of EOAZ, the peak-to-peak amplitudes of CAPs following 180 min exposure of the nerve to the drug were reduced significantly, to 75.3 +/- 7.36%, 50.45 +/- 2.17% and 0% respectively, of control value. Conduction velocity was reduced significantly by 300, 600 and 2000 microg/ml of EOAZ, at 180 min, to 83.61 +/- 3.28%, 64.06 +/- 8.21% and 22.7 +/- 5.79%, respectively, of control value. All these effects developed slowly and were reversible upon a 180-min wash.

Action Potentials↗
PubMed1997

Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations.

The 4'-hydroxylation of S-mephenytoin is polymorphic in man. The poor metabolizer (PM) phenotype exhibits a lower frequency in Caucasians (2-5%) compared to Oriental populations (13-23%). Previous studies from our laboratory have described two mutations (CYP2C19m1 and CYP2C19m2) which account for approximately 100% of Oriental and approximately 85% of Caucasian PM alleles. The present study examined whether the genotype predicted the phenotype in Japanese, Filipino and Saudi Arabian populations, and compared the frequencies of the defective CYP2C19 alleles in these populations with those found in European-Americans, Chinese-Taiwanese, and African-Americans from North Carolina. Among 53 Japanese, 15% were PMs and among 52 Filipinos 23% were PMs. Among 97 Saudi Arabians, only two were PMs. There was a complete concordance between genotype and phenotype in all three populations. The incidence of CYP2C19m1 was 0.23 (95% confidence limits 0.15-0.31) in Japanese, 0.39 (95% confidence limits 0.29-0.48) in Filipinos, 0.32 (95% confidence limits 0.26-0.38) in Chinese-Taiwanese, 0.15 (95% confidence limits 0.10-0.20) in Saudi Arabians, 0.13 (95% confidence limits 0.08-0.17) in European-Americans, and 0.25 in African-Americans from North Carolina (95% confidence limits (0.14-0.31). The incidence of CYP2C19m1 in Saudi Arabians was similar to that found in European-Americans, and significantly lower than that found in Oriental populations or African-Americans (p < 0.05). CYP2C19m2 was not found in European-Americans, Saudi Arabians or African-Americans (95% confidence limits 0-0.014). The incidence of CYP2C19m2 in the three Oriental populations ranged from 0.10 (95% confidence limits 0.05-0.17) in Japanese and 0.08 (95% confidence limits 0.03-0.13) in Filipinos to 0.06 (95% confidence limits 0.03-0.08) in Chinese-Taiwanese.

Alleles↗
PubMed1995

Genetic analysis of the S-mephenytoin polymorphism in a Chinese population.

The 4'-hydroxylation of S-mephenytoin exhibits a polymorphism in humans, with the poor metabolizer phenotype exhibiting a lower frequency in white (3% to 5%) than in Oriental populations (13% to 23%). Two mutations in CYP2C19 (CYP2C19m1 and CYP2C19m2) have recently been described that account for approximately 85% of white and 100% of Japanese poor metabolizers. This study examines whether these mutations account for the poor metabolizer phenotype in the Chinese population. The metabolism of S-mephenytoin exhibited a bimodal distribution in 244 unrelated Chinese subjects, although the distribution of the two phenotypes overlapped. In 75 selected Chinese subjects, CYP2C19 genotype analysis predicted the phenotype with 100% accuracy. The frequency of the poor metabolizer phenotype was approximately 11% (95% confidence interval 7% to 15%). The frequency of the CYP2C19m1 allele was 0.289, whereas that of CYP2C19m2 was 0.044. Homozygous extensive metabolizers had slightly lower ratios of S/R-mephenytoin compared with heterozygous extensive metabolizers, showing a gene-dosage effect. These data show the advantages of genotype analysis in investigations of the mephenytoin phenotype in Oriental subjects.

Adolescent↗
PubMed1995

A multifamily study on the relationship between CYP2C19 genotype and s-mephenytoin oxidation phenotype.

It has recently been shown that the most common mutation (named m1) in both Caucasian and Japanese poor metabolizers (PM) of S-mephenytoin is a single base pair mutation (G-->A) in exon 5 of the CYP2C19 gene. In Japanese, a second defective allele of CYP2C19 named m2 consists of a G-->A mutation in exon 4. In the present study, we have investigated the inheritance of the CYP2C19 wild type allele (wt) and the two defective alleles (m1 and m2) in families of 11 Danish PM probands. The study was carried out for two principal reasons. First, we wanted to confirm the autosomal recessive inheritance of the defective alleles, and second, we wanted to examine the specificity and sensitivity of the CYP2C19 genotyping test. Individuals were phenotyped by measuring the ratio of S/R mephenytoin excreted in the urine after administration of mephenytoin, and genotyping was carried out by a PCR-based DNA amplification procedure. The genotypes of nine of the 11 probands were consistent with their phenotypes. Eight were homozygous m1/m1, and one was heterozygous m1/m2. The genotypes of two putative PM probands (wt/m1) were not consistent with their phenotypes. On the basis of extended phenotyping (additional late urine collections (24-36 h) and acidification of urine), one of these could probably be reclassified as an extensive metabolizer (EM) while the other was considered to be a true PM. This suggests the presence of an additional unknown mutant allele in the latter. Seven of the 41 phenotyped relatives in the 11 families were phenotyped as PMs, and with the exception of the father of family 10, their genotypes (m1/m1) were consistent with their phenotypes. Extended phenotyping (acidification of urine) suggested that the father of family 10 in fact is an EM and hence that his genotype (wt/m1) is concordant with his phenotype. Thus, the specificity of genotyping tests for PM was 100%, while the sensitivity was 15/16 or 94%. Our study provides unequivocal evidence for autosomal recessive inheritance of the PM trait.

Adult↗
PubMed1994

The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans.

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans, with the poor metabolizer trait being inherited in an autosomal recessive fashion. There are large interracial differences in the frequency of the poor metabolizer phenotype, with Oriental populations having a 5-fold greater frequency compared to Caucasians. Impaired metabolism of mephenytoin and a number of other currently used drugs results from a defect in a cytochrome P450 enzyme recently identified as CYP2C19. Attempts over the past decade to define the molecular genetic basis of the polymorphism have, however, been unsuccessful. We now report that the principal defect in poor metabolizers is a single base pair (G-->A) mutation in exon 5 of CYP2C19, which creates an aberrant splice site. This change alters the reading frame of the mRNA starting with amino acid 215 and produces a premature stop codon 20 amino acids downstream, which results in a truncated, non-functional protein. We further demonstrate that 7/10 Caucasian and 10/17 Japanese poor metabolizers are homozygous for this defect, indicating that this is the major defect responsible for the poor metabolizer phenotype. Finally, the familial inheritance of the deficient allele was found to be concordant with that of the phenotypic trait.

Alternative Splicing↗
PubMed1994

Photoaffinity labeling of the Ah receptor with 3-[3H]methylcholanthrene and formation of a 165-kDa complex between the ligand-binding subunit and a novel cytosolic protein.

The aromatic hydrocarbon (Ah) receptor is a cytosolic protein that binds halogenated ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and nonhalogenated ligands such as 3-methylcholanthrene (MC) and benzo[a]pyrene. The best characterized biological response mediated by the Ah receptor is induction of cytochrome P4501A1 (CYP1A1). Photoaffinity labeling of the Ah receptor has been reported only with halogenated ligands such as TCDD and some of its iodinated derivatives. In this study, photolabeling of the Ah receptor was achieved with the nonhalogenated aromatic hydrocarbon [3H]MC. Sources of Ah receptor were the mouse hepatoma cell line Hepa-1c1c9 and the human colon adenocarcinoma line LS180. Cytosolic fractions either were used in a crude form or were enriched by glycerol density gradient centrifugation. These then were incubated with [3H]MC, irradiated with UV light (> 300 nm), precipitated with acetone, and analyzed by SDS-polyacrylamide gel electrophoresis. The yield of photoadduct formation was lower with [3H]MC (approximately 1%) compared with [3H]TCDD (3.5%) in Hepa-1c1c9 cells. The same was true in LS180 cells, i.e. the yield was 0.2% for [3H]MC versus 5.48 +/- 0.26% for [3H]TCDD. The relative molecular mass of the [3H]MC-labeled receptor estimated by SDS-polyacrylamide gel electrophoresis was 94,600 +/- 2,400 (mean +/- S.E.) for Hepa-1c1c9 cells and 113,600 +/- 3,200 for LS180 cells; these are the same molecular masses as determined by photolabeling with [3H]TCDD. In velocity sedimentation assays of mouse cytosol, [3H]MC binds specifically to two cytosolic proteins: the 4 S carcinogen-binding protein and the Ah receptor (9 S). However, no photolabeling of the 4 S protein was detected in our experiments. [3H]MC photolabeling of the human Ah receptor from LS180 cells was detected only in experiments using enriched cytosolic preparations. In addition to the 95-kDa ligand-binding subunit, a specifically radiolabeled protein of 164,900 +/- 5,800 kDa was also detected in Hepa-1c1c9 cytosol photolabeled with [3H]MC, suggesting cross-linking, by MC, of another subunit of the multimeric Ah receptor complex to the ligand-binding subunit. Immunochemical analysis showed that the ligand-binding subunit of the Ah receptor is one component of the 165-kDa complex. The other protein in the complex could not be identified with antibodies to the heat shock proteins hsp90 or hsp70 or with antibodies to the p59 protein or Ah receptor nuclear translocator protein. The identity and function of the protein that becomes cross-linked to the ligand-binding subunit require further investigation.

Affinity Labels↗
PubMed1994

Biochemistry and molecular biology of the human CYP2C subfamily.

The cytochromes P450 (CYP) are a superfamily of hemoproteins which metabolize foreign chemicals as well as a number of endogenous compounds such as steroids. The human CYP2C subfamily appears to principally metabolize a number of clinically used drugs. Four members of this subfamily have been identified in humans: CYP2C8, CYP2C9, CYP2C18, and CYP2C19. CYP2C9 is important in the metabolism certain of therapeutically used drugs including the anticoagulant drug warfarin and a number of nonsteroidal antiinflammatory drugs. A number of allelic variants of CYP2C9 exist in humans, but the effects of these allelic variants on metabolism in vivo remain to be determined. A well-characterized genetic polymorphism occurs in the 2C subfamily which is associated with the metabolism of the anticonvulsant drug mephenytoin. In population studies, individuals can be segregated into extensive and poor metabolizers of mephenytoin. Poor metabolizers are unable to 4'-hydroxylate the S-enantiomer of mephenytoin. There are marked interracial variations in the frequency of the poor metabolizer phenotype which represents 3-5% of Caucasians, but 18-23% of Oriental populations. The mechanism of this polymorphism has been recently elucidated. The enzyme responsible for S-mephenytoin metabolism has been shown to be CYP2C19, and two defects in the CYP2C19 gene have been described in poor metabolizers. The first defect, CYP2C19m1, consists of the creation of an aberrant splice site in exon 5. This defect accounts for approximately 75-85% of Caucasian and Japanese poor metabolizers. A second defect, CYP2C19m2, has been found only in Oriental populations and accounts for the remaining 25% of poor metabolizers in Japanese populations. The availability of genotyping tests for this polymorphism will enhance the assessment of the role of this pathway in clinical studies.

Amino Acid Sequence↗
PubMed1993

Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18.

There is a genetic polymorphism in humans in the metabolism of S-mephenytoin which has been suggested to be mediated by either CYP2C18 or CYP2C9. We have isolated genomic clones for CYP2C9 and CYP2C18 from the liver of an individual phenotyped in vitro as an extensive metabolizer of S-mephenytoin. Analysis of the genes reveals nine coding exons spanning approximately 55 kb. The intron-exon organization was similar to that of other members of the CYP2C subfamily. Analysis of 2200 bp of 5' upstream sequence for CYP2C9 and 1300 bp 5' upstream sequence for CYP2C18 reveals canonical TATA boxes situated 57 bp upstream from the first codon, multiple consensus sequences for glucocorticoid regulatory elements, and identification of a 15 base sequence with high homology to a 5'-flanking sequence responsible for barbiturate-inducible expression of P450BM-3 in Bacillus megaterium. The upstream region for CYP2C9 was highly homologous (75%) to that of human CYP2C8 through most of the 2200 bp sequenced, but the upstream region of CYP2C18 was similar to CYP2C8 and CYP2C9 for only the first 200 bases. The availability of the sequences of the upstream regions and intron-exon junctions of CYP2C9 and CYP2C18 will allow future analysis of these genes in humans which differ in their ability to metabolize S-mephenytoin and other drugs.

Aryl Hydrocarbon Hydroxylases↗
PubMed1993

Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe.

The regio- and stereoselectivity of warfarin metabolism have been used to assess structure-function relationships of human P4502C subfamily members. Metabolism was investigated using a yeast cDNA expression system in which full length cDNAs for P4502C8, -2C9 (alleles Arg144 Tyr358 Ile359 Gly417 and Arg144 Tyr358 Leu359 Gly417), -2C18 (alleles Thr385 and Met385), and -2C19 were expressed. Additionally, two mutations reported in other P4502C9/2C10 alleles were individually introduced into P4502C9 by site-directed mutagenesis, to yield Cys144 Tyr358 Ile359 Gly417, Arg144 Tyr358 Ile359 Asp417, and Arg144 Cys358 Ile359 Gly417, which were expressed in yeast; their ability to metabolize warfarin was then studied. Warfarin metabolism by purified preparations of P4502C9 allele Arg144 Tyr358 Ile359 Gly417 and its Leu359 mutant was also investigated in reconstituted systems. Both alleles of P4502C18 were regioselective for 4'-hydroxywarfarin, without any significant stereoselectivity. Both also metabolized warfarin at the 6-position, but to a lesser extent, and metabolism at this site was stereoselective for (R)-warfarin. P4502C8 metabolized warfarin at the 7-position and was stereospecific for (R)-warfarin. It also metabolized warfarin to a lesser extent at the 4'-position, and metabolism at this site was stereoselective for (R)-warfarin. P4502C19 was regioselective for 6- and 8-hydroxywarfarin and was stereoselective for (R)-warfarin. The highly conservative mutation of Ile359 to Leu359 in P4502C9 profoundly altered the regio- and stereoselectivity of warfarin metabolism, from regioselective for 7-hydroxywarfarin, with stereospecificity for (S)-warfarin, to regioselective for 4'-hydroxywarfarin, with stereoselectivity for (R)-warfarin, which was confirmed in a reconstituted system using purified recombinant enzymes. In contrast, individual mutations of P4502C9 of Arg144 to Cys, Tyr358 to Cys, and Gly417 to Asp did not markedly affect the regio- or stereoselectivity of warfarin metabolism, although the overall rates of warfarin metabolism were apparently increased by these changes. We conclude that residue 359 is at the substrate binding site of P4502C9, whereas residues 144, 358, and 417, and residue 385 of P4502C18, are not.

Alleles↗
PubMed1992

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)

Acetaminophen↗
PubMed1992

Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase.

Acetaminophen is eliminated primarily by glucuronidation, thereby avoiding cytochrome P450-catalyzed bioactivation to a toxic reactive intermediate. Previous studies have shown that UDP-glucuronosyltransferase-deficient Gunn rats are more susceptible to acetaminophen toxicity than normal Wistar controls, from which the Gunn strain was derived. However, the Gunn and Wistar strains are not congenic, and differences in toxicologic susceptibility could be due in part to genetic differences other than UDP-glucuronosyltransferase activity. Accordingly, acetaminophen (750 mg/kg, ip) was administered to congenic RHA rats with normal (homozygous, RHA/++), moderately deficient (heterozygous, RHA/j+), and severely deficient (homozygous jaundiced, RHA/jj) activities of bilirubin UDP-glucuronosyltransferase. Acetaminophen metabolites were measured by high-performance liquid chromatography and production of the acetaminophen glucuronide conjugate was quantified by the area under plasma concentration-time curve (AUC) from 0 to 2 hr, standardized by the AUC value for acetaminophen in the same animal (glucuronidation ratio = AUC acetaminophen glucuronide/AUC acetaminophen). The 0- to 2-hr time period for AUC calculations was necessitated by the accumulation at later time points of glucuronide and sulfate conjugates in the plasma of animals experiencing severe nephrotoxicity. Acetaminophen bioactivation was quantified by the 24-hr urinary recovery of glutathione-derived conjugates. Hepatotoxicity and nephrotoxicity were assessed respectively by the peak concentrations of plasma alanine aminotransferase (ALT) and blood urea nitrogen (BUN). Glucuronidation of acetaminophen in RHA/jj rats (0.065 +/- 0.005) (mean +/- SE) was reduced 63% compared to the RHA/++ controls (0.17 +/- 0.01) (p < 0.05). RHA/jj rats demonstrated respective 230- and 7-fold increases in the peak plasma concentrations of ALT (17144 +/- 1014 vs 75 +/- 10) and BUN (128 +/- 23 vs 18.4 +/- 0.2) compared to congenic normal controls (RHA/++) (p < 0.05). Heterozygous animals (RHA/j+) demonstrated intermediary toxicity for both parameters (ALT = 2029 +/- 1581, BUN = 41 +/- 16, p < 0.05). Decreased glucuronide production correlated with elevations in ALT (r = -0.86, p < 0.001), while increased acetaminophen bioactivation correlated directly with both elevated ALT (r = 0.93, p < 0.001) and BUN (r = 0.83, p = 0.001). These results using congenic controls demonstrate that the enhanced susceptibility of UDP-glucuronosyltransferase-deficient rats to acetaminophen toxicity is due to decreased glucuronidation resulting in enhanced bioactivation, rather than to other unappreciated genetic differences.

Acetaminophen↗
PubMed1989

Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency.

Glucuronidation is the major pathway for elimination of acetaminophen, diverting it from the toxifying pathway catalyzed by cytochromes P-450. A genetic deficiency in bilirubin UDP-glucuronyl transferase may predispose humans and animals to the toxicity of drugs that are extensively glucuronidated, if other glucuronyl transferase isoenzymes are concurrently deficient. Homozygous and heterozygous Gunn rats are, respectively, severely and moderately deficient in glucuronyl transferase. Acetaminophen (500 mg per kg) was administered intraperitoneally to homozygous and heterozygous Gunn rats and to Wistar controls. Hepatic and renal cellular damage was assessed by peak plasma concentrations of ALT and blood urea nitrogen, respectively. Homozygous and heterozygous Gunn rats showed, respectively, 115-fold and 9-fold higher ALT concentrations compared to Wistar controls. Blood urea nitrogen was elevated only in the homozygous Gunn rats (3-fold). Biotransformation of acetaminophen was measured by high-performance liquid chromatography. Acetaminophen glucuronidation was decreased by 72 and 35% (p less than 0.05), respectively, in the homozygous and heterozygous Gunn rats compared with Wistar controls. Production of acetaminophen glucuronide correlated negatively with ALT concentration (r = -0.89, p less than 0.001). Production of glutathione-derived metabolites, reflecting acetaminophen bioactivation, was 2 to 3-fold higher in the Gunn rats (p less than 0.05) and correlated with ALT concentrations (r = 0.90, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1988

Deficiency in bilirubin UDP-glucuronyl transferase as a genetic determinant of acetaminophen toxicity.

Over 60% of the analgesic/antipyretic drug acetaminophen is eliminated by glucuronidation, which competes with a toxifying pathway involving cytochromes P-450-catalyzed bioactivation to a hepatotoxic reactive intermediate. A genetic deficiency of bilirubin UDP-glucuronyl transferase (GT) occurs in 5 to 7% of the population (Gilbert's disease, Crigler-Najjar syndrome) and this could predispose such people to acetaminophen hepatotoxicity. This hypothesis was evaluated in the homozygous Gunn rat, which is similarly deficient in GT, and the heterozygous Gunn rat, which has intermediary GT activity. Acetaminophen, 1 g/kg, was administered by gavage to animals 6 and 11 weeks of age, and age-matched Wistar rats as controls. Hepatic and renal cellular damage were assessed by respective increases in the peak plasma concentration of alanine aminotransferase and the blood urea nitrogen concentration, and confirmed by histological examination. Acetaminophen and metabolites were measured by high-performance liquid chromatography. Compared to Wistar controls, Gunn rats demonstrated up to a 110-fold greater hepatotoxic response to acetaminophen, with significantly lower production of the glucuronide conjugate and higher plasma concentrations of acetaminophen. Elevated acetaminophen concentrations correlated positively with both increased production of the acetaminophen-cysteine conjugate, reflecting bioactivation and hepatotoxicity. Older Gunn but not Wistar rats showed up to 26-fold more hepatotoxicity compared to their younger counterparts. In younger animals, heterozygotes demonstrated intermediary hepatotoxicity between homozygotes and Wistar controls. Hepatotoxicity was similar in the older heterozygotic and homozygotic Gunn rats, as was renal toxicity, which was enhanced 2- to 3-fold over controls. These results indicate that a genetic deficiency in bilirubin GT can be an important determinant of acetaminophen bioactivation and toxicity.

Acetaminophen↗