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Biomedical subjects

R J Ferguson

Publications and source records attributed to R J Ferguson.

82 records · Page 5Linked to original sources
PubMedDate not supplied

The latero-medial inferior pontine syndrome.

A case is presented with a pontine vascular lesion involving the V, VI, VII, and VIII cranial nerves. The diagnostic evaluation included audiometry and electronystagmography as well as arteriography, pneumoencephalography, and brain scan. Total deafness developed in the involved ear and was present for seven weeks before complete recovery occurred. Electronystagmographic findings consistent with a brain stem lesion also resolved following recovery of the patient. Audiometry and electronystagmography are described and documented for the first time in a report of a patient with a latero-medial inferior pontine syndrome. A discussion of some of the unique features of the brain stem vasculature and its relationship to clinical syndromes involving the brain stem is given.

Audiometry↗
PubMedDate not supplied

Acetylator genotype-dependent expression of arylamine N-acetyltransferase and N-hydroxyarylamine O-acetyltransferase in Syrian inbred hamster intestine and colon. Identity with the hepatic acetylation polymorphism.

Human epidemiological studies suggest an association between rapid acetylator phenotype and the incidence of colorectal cancer. Genetic regulation of acetyl coenzyme A-dependent N-acetyltransferase (NAT) and O-acetyltransferase (OAT) enzymatic activities may play a role in the metabolic activation of arylamine chemicals in the intestine and colon. In this study, the inheritance of acetyltransferase activity in the intestine and colon was investigated in the Syrian inbred hamster model. Relatively high levels of both arylamine NAT and N-hydroxyarylamine OAT activities were expressed in hamster intestine and colon cytosols, at levels similar to those in the liver. Acetylator genotype-dependent levels of NAT activity were expressed towards p-aminobenzoic acid and the carbocyclic arylamine carcinogens 2-aminofluorene (AF), 4-aminobiphenyl, and beta-naphthylamine. However, acetylator genotype-independent activity was found with the heterocyclic arylamine carcinogens 2-aminodipyrido[1,2-a:3',2'd]imidazole, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, and 2-amino-9H-pyrido-[2,3,b]indole. F1 hybrid heterozygous acetylator progeny expressed unimodal levels of acetyltransferase activity intermediate between the homozygous rapid and slow acetylator parental strains. F2 generation progeny segregated into three modes (low, intermediate, and high) in a ratio of 1/2/1, and both sets of backcrosses yielded bimodal distributions of low and intermediate or high and intermediate in equal ratios. The genetic data is consistent with simple autosomal Mendelian inheritance of two codominant alleles (rapid and slow) at a single genetic locus, the polymorphic acetyltransferase gene. Levels of N-hydroxy-2-aminofluorene OAT activity were acetylator genotype-dependent in liver, intestine, and colon cytosols, which correlated well with AF NAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMedDate not supplied

Identification and kinetic characterization of acetylator genotype-dependent and -independent arylamine carcinogen N-acetyltransferases in hamster bladder cytosol.

Recent studies from our laboratory have shown relatively high levels of polymorphic N-acetyltransferase (NAT)(EC 2.3.1.5) activity toward carcinogenic arylamines in urinary bladder cytosol of humans and in the inbred hamster model of the N-acetylation polymorphism. The expression of this polymorphism is of interest because of the higher incidence of bladder cancer among human slow acetylators with documented exposures to arylamine bladder carcinogens. In this study, arylamine NAT activity was partially purified and characterized in inbred hamster urinary bladder cytosols of defined acetylator genotype. Acetylator gene-dose response relationships were observed for the N-acetylation of p-aminobenzoic acid, p-aminosalicyclic acid, and the arylamine carcinogens 2-aminofluorene, 4-aminobiphenyl, and beta-naphthylamine in hamster bladder cytosol. Partial purification of hamster bladder cytosol by anion-exchange fast protein liquid chromatography yielded two NAT isozymes that catalyzed the N-acetylation of each of the arylamine substrates. The catalytic activity of the first isozyme was acetylator genotype-dependent (polymorphic), whereas the second isozyme appeared to be acetylator genotype-independent (monomorphic). Catalytic activities between homozygous rapid, heterozygous, and homozygous slow acetylator genotypes were compared with respect to both initial rates and apparent maximum velocities. Comparison of homozygous rapid and slow acetylator bladder cytosol showed that the apparent Vmax for 2-aminofluorene NAT activity was significantly higher in rapid than slow acetylators (6-fold in cytosol, 50-fold in the polymorphic NAT isozyme). These results suggest a key role for a polymorphic NAT isozyme, regulated by the acetylator genotype and expressed in urinary bladder cytosol, in the initiation of bladder cancer via arylamine carcinogens.

4-Aminobenzoic Acid↗
PubMedDate not supplied

Kinetic characterization of acetylator genotype-dependent and -independent N-acetyltransferase isozymes in homozygous rapid and slow acetylator inbred hamster liver cytosol.

Acetyl-coenzyme A (AcCoA)-dependent arylamine N-acetyltransferase (NAT) activity (EC 2.3.1.5) was examined in liver cytosol derived from homozygous rapid acetylator (Bio. 87.20) and homozygous slow acetylator (Bio. 82.73/H) Syrian inbred hamsters. Expression of NAT activity toward p-aminobenzoic acid (PABA), 2-aminofluorene (AF), and 4-aminobiphenyl (ABP) was acetylator genotype-dependent, whereas N-acetyltransferase activity toward isoniazid was acetylator genotype-independent. Two isozymes of NAT activity were partially purified by anion exchange fast protein liquid chromatography from the hepatic cytosol of both homozygous rapid and homozygous slow acetylator hamsters. The first eluting NAT isozyme exhibited a polymorphic expression toward AF, ABP, and PABA although the second eluting NAT isozyme exhibited a monomorphic expression across acetylator genotypes toward the same substrates. Determination of Michaelis-Menten kinetic constants in hepatic cytosol of homozygous rapid and slow acetylator hamsters suggests that PABA, AF, and ABP NAT activities were acetylator genotype-dependent because of catalysis by polymorphic NAT isozyme that is both an apparent Km and Vmax variant, whereas, the acetylator genotype-independent expression of isoniazid NAT activity appeared to result from catalysis via a common monomorphic NAT isozyme in both acetylator genotypes. Additional kinetic studies on the partially purified NAT isozymes of homozygous rapid and slow acetylator hamster liver confirmed that the polymorphic NAT isozyme exhibited a substantially higher apparent maximum velocity in homozygous rapid acetylators than slow acetylators toward PABA, AF, and ABP as well as acetylator genotype-related differences in the apparent Km toward each of these substrates. In contrast, the monomorphic NAT isozyme of both acetylator genotypes showed apparent Vmax levels of NAT activity that did not vary with acetylator genotype. Furthermore, the monomorphic NAT isozyme did not show acetylator genotype-related variations in apparent Km toward the arylamine carcinogens AF and ABP, although differences were noted for PABA and AcCoA. These results suggest that the acetylator genotype-dependent expression of AcCoA-dependent NAT activity in hamster hepatic cytosol toward arylamines is primarily accountable by structural variants (allozymes) of polymorphic NAT under the genetic regulation of the acetylator gene locus. The acetylator genotype-independent expression of isoniazid NAT activity is attributable to a common monomorphic NAT isozyme in both acetylator genotypes.

4-Aminobenzoic Acid↗
PubMedDate not supplied

The ultrastructure of human osteosarcoma: a study of nine cases.

Electron microscopic study of 9 osteosarcomas corroborates the light microscopic observation that cells with osteoblastic, chondroblastic and fibroblastic features occur in osteosarcomas. Two types of multinucleated giant cells were observed, one was osteoclast-like. The other had anaplastic and degenerative changes. The intercellular matrix is composed of collagen fibers, amorphous ground substance with osteoid and tumor bone. Contrary to many previous electron microscopic reports, osteosarcomas contain more than one cell type.

Adolescent↗
PubMedDate not supplied

The role of acetylator genotype on hepatic and extrahepatic acetylation, deacetylation, and sulfation of 2-aminofluorene, 2-acetylaminofluorene, and N-hydroxy-2-acetylaminofluorene in the inbred hamster.

In vitro rates of acetylation, deacetylation, and sulfation were measured with carcinogenic arylamine, arylamide, and arylhydroxamic acid substrates using enzyme preparations derived from inbred hamster tissues of known acetylator genotype. Homozygous rapid acetylators (Bio. 87.20), heterozygous acetylators (Bio. 87.20 X Bio. 82.72/H F1), and homozygous slow acetylators (Bio. 82.73/H) did not differ significantly with respect to paraoxon-resistant intermolecular N,N-transacetylation reactions from N-hydroxy-2-acetylaminofluorene to 4-aminoazobenzene in tissue cytosol. Similarly, they did not differ with respect to paraoxon-sensitive, microsomal N-hydroxy-2-acetylaminofluorene and 2-acetylaminofluorene deacetylase, and cytosolic N-hydroxy-2-acetylaminofluorene sulfotransferase activity. However, a gene dose-response relationship was observed in the same animals for cytosolic acetyl coenzyme A-dependent 2-aminofluorene N-acetyltransferase activity. Partial purification of liver cytosol yielded two paraoxon-resistant isozyme forms of acetyltransferase activity. The rates of one isozyme were acetylator genotype dependent (polymorphic), whereas the rates of the second isozyme appeared to be acetylator genotype independent (monomorphic). Acetyl coenzyme A-dependent 2-aminofluorene N-acetyltransferase activity was catalyzed at high rates by both isozymes, whereas transacetylation of 4-aminoazobenzene by various acyl donors (N-hydroxy-2-acetylaminofluorene, N-hydroxy-4-acetylaminobiphenyl, and acetyl coenzyme A) was catalyzed primarily (but not exclusively) by the monomorphic acetyltransferase isozyme. These results provide further information concerning the importance of acetylator genotype in the metabolism of carcinogenic arylamines and their metabolites.

2-Acetylaminofluorene↗
PubMedDate not supplied

Genetic control of acetyl coenzyme A-dependent arylamine N-acetyltransferase, hydrazine N-acetyltransferase, and N-hydroxy-arylamine O-acetyltransferase enzymes in C57BL/6J, A/J, AC57F1, and the rapid and slow acetylator A.B6 and B6.A congenic inbred mouse.

Acetyl coenzyme A-dependent N-acetyltransferase and O-acetyltransferase activities were examined in liver cytosols derived from homozygous rapid acetylator C57BL/6J and A.B6 congenic inbred mouse strains, from homozygous slow acetylator A/J and B6.A congenic inbred mouse strains, and from the (C57BL/6J x A/J)F1 heterozygous acetylator hybrid mouse strain. Acetylator genotype-dependent N-acetyltransferase activity was exhibited for the N-acetylation of p-aminobenzoic acid, 2-aminofluorene, and 4-aminobiphenyl. In contrast, levels of isoniazid N-acetyltransferase and N-hydroxy-3,2'-dimethyl-4-aminobiphenyl O-acetyltransferase activities in mouse liver cytosol appeared to be independent of the arylamine Nat acetylator gene. Although cytosolic N-acetyltransferase activities differed about 2-fold between the parental C57BL/6J and A/J strains for p-aminobenzoic acid, 2-aminofluorene, and 4-aminobiphenyl, the same N-acetyltransferase activities differed about 6-7-fold between the homozygous rapid acetylator A.B6 and the homozygous slow acetylator B6.A congenic inbred strains. Partial purification of acetyl coenzyme A-dependent arylamine N-acetyltransferase activity in the five inbred mouse strains showed one major paraoxon-resistant enzyme in liver cytosol in each of the rapid and slow acetylator mouse strains examined. Levels of partially purified 2-aminofluorene and 4-aminobiphenyl N-acetyltransferase activity were about 7-fold higher in the A.B6 than the B6.A congenic inbred strain. Partial purification of acetyl coenzyme A-dependent isoniazid N-acetyltransferase activity showed catalysis by a paraoxon-resistant enzyme(s) distinct from the major arylamine N-acetyltransferase enzyme(s). These results suggest that isoniazid N-acetyltransferase(s) in mouse liver cytosol is a product of a separate gene that segregates independently of the arylamine Nat gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyl-CoA C-Acetyltransferase↗
PubMedDate not supplied

Cloning, expression, and functional characterization of two mutant (NAT2(191) and NAT2(341/803)) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles.

The N-acetylation polymorphism segregates individuals into rapid, intermediate, and slow acetylator phenotypes via monogenic inheritance at the NAT2 locus. In a previous study (Arch. Toxicol. 67, 445-452, 1993), we uncovered discrepancies between apparent NAT2 acetylator genotype based on polymerase chain reaction-restriction fragment length polymorphism analysis, in vitro colon arylamine N-acetyltransferase activity, and expected frequency of slow acetylator phenotype in African-Americans, which suggested the presence of not yet defined mutant NAT2 alleles. Two novel NAT2 alleles were discovered after cloning and sequencing of NAT2 polymerase chain reaction products. One allele (NAT2(191)) contained a point mutation at nucleotide 191 [G-->A (Arg-->Gln)], whereas the other allele (NAT2(341/803)) contained two point mutations [341T-->C (Ile-->Thr); 803A-->G (Lys-->Arg)]. The two mutant NAT2 and the NAT2wt alleles were expressed in a prokaryotic expression system. Both the NAT2(191) and NAT2(341/803) mutant alleles expressed functional N-acetyltransferases capable of catalyzing both arylamine N-acetylation and the metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene. However, the NAT2(191) and NAT2(341/803) each exhibited significantly lower N- and O-acetylation capacity and were intrinsically less stable than NAT2wt.

Acetylation↗