Studies on the structure and regulation of two highly similar genes in the alcohol-inducible cytochrome P-450 subfamily.
dc.contributor.author | Khani, Shahrokh Charles | |
dc.contributor.advisor | Coon, Minor J. | |
dc.date.accessioned | 2016-08-30T16:47:12Z | |
dc.date.available | 2016-08-30T16:47:12Z | |
dc.date.issued | 1989 | |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:8920562 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/128325 | |
dc.description.abstract | Liver microsomal cytochrome P-450s are a group of monooxygenases that are responsible for the metabolism of a wide variety of drugs and other foreign compounds in many species. Of particular biomedical interest is an alcohol-inducible P-450, designated as P-450 3a in rabbit, which catalyzes the oxidation of a number of compounds, including alcohols, acetone, and nitrosamines, and is suspected of playing a role in the conversion of acetaminophen, isoniazid, and some fluorine-containing anesthetics into hepatotoxic intermediates. The study presented in this thesis was concerned with the isolation and characterization of the genes encoding P-450 3a and a previously uncharacterized P-450 3a-like protein. As deduced from the sequence of two overlapping cDNAs, p3a-1 and p3a-2, encoding rabbit P-450 3a, this cytochrome was found to be 492 residues in length with a molecular weight of 56,820. The amino acid sequence of P-450 3a is approximately 50-60% identical to the sequence of rabbit P-450s 1, 2, and 3b and therefore can be grouped with these isozymes into a single family. With the use of 3a cDNA as a hybridization probe, at least two mRNAs differing in size were detected in rabbit liver. Treatment of rabbits with imidazole, which is known to cause a 4.5-fold increase in 3a protein, resulted in only a transient increase in the 3a mRNA level, indicating that the induction of 3a protein results largely from an increase in translational efficiency or in the half-life of the 3a protein. Clones for two distinct genomic loci, genes 1 and 2, were characterized and shown to encode, respectively, P-450 3a and a previously unidentified P-450 that is 97% identical in sequence to 3a. The genes are believed to share a common ancestral origin with one another and with the phenobarbital-inducible P-450 genes since the corresponding nine exons and their splice junctions in all of these genes are arranged identically with respect to the mRNA. Gene 2 mRNA is present in liver only, whereas gene I mRNA occurs in both liver and kidney. The differential distribution of the two gene transcripts may be related to the significant differences found in the 5$\sp\prime$ flanking sequences of genes 1 and 2. | |
dc.format.extent | 93 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Alcohol | |
dc.subject | Cytochrome | |
dc.subject | Genes | |
dc.subject | Highly | |
dc.subject | Inducible | |
dc.subject | Regulation | |
dc.subject | Similar | |
dc.subject | Structure | |
dc.subject | Studies | |
dc.subject | Subfamily | |
dc.subject | Two | |
dc.title | Studies on the structure and regulation of two highly similar genes in the alcohol-inducible cytochrome P-450 subfamily. | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Biochemistry | |
dc.description.thesisdegreediscipline | Pure Sciences | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/128325/2/8920562.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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