Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
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Target Concepts:
Gene/Protein
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Query: EC:2.3.1.28 (
chloramphenicol acetyltransferase
)
5,100
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The effects of mono(2-ethyl-5-oxohexyl)phthalate [ME(O)HP], a di(
2-ethylhexyl
)phthalate (DEHP) metabolite and a potent peroxisomal inducer, on the mitochondrial beta-oxidation were investigated. In isolated rat hepatocytes, ME(O)HP inhibited long chain fatty acid oxidation and had no effect on the ketogenesis of short chain fatty acids, suggesting that the inhibition occurred at the site of carnitine-dependent transport across the mitochondrial inner membrane. In rat liver mitochondria, ME(O)HP inhibited carnitine acyltransferase I (
CAT I
; EC 2.3.1.21) competitively with the substrates palmitoyl-CoA and octanoyl-CoA. An analogous treatment of mouse mitochondria produced a similar competitive inhibition of palmitoyl-CoA transport whereas ME(O)HP exposure with guinea pig and human liver mitochondria revealed little or no effect. The addition of clofibric acid, nafenopin or methylclofenopate revealed no direct effects upon
CAT I
activity. Inhibition of transferase activity by ME(O)HP was reversed in mitochondria which had been solubilized with octyl glucoside to expose the latent form of carnitine acyltransferase (
CAT II
), suggesting that the inhibition was specific for
CAT I
. Our results demonstrate that in vitro ME(O)HP inhibits fatty acid oxidation in rat liver at the site of transport across the mitochondrial inner membrane with a marked species difference and support the idea that induction of peroxisome proliferation could be due to an initial biochemical lesion of the fatty acid metabolism.
...
PMID:In vitro inhibition of carnitine acyltransferase activity in mitochondria from rat and mouse liver by a diethylhexylphthalate metabolite. 845 57
Peroxisome proliferators are nongenotoxic carcinogens capable of causing rapid transcriptional activation of genes comprising the rodent beta-oxidation pathway. Numerous compounds, such as hypolipidemic drugs, herbicides, plasticizers, and analgesics have been identified as peroxisome proliferators in rodents. We have developed a whole-cell in vitro assay to detect peroxisome proliferators in approximately 48 h. A promoter::
chloramphenicol acetyltransferase
(
CAT
) fusion construct for rat acyl-CoA oxidase (ACOX), the rate-limiting enzyme in the peroxisomal beta-oxidation pathway, was stably transfected into the rat liver cell line H-4-II-E. Treatment of the recombinant cell line (ACOX::
CAT
) with peroxisome proliferators, WY 14,643, clofibrate, di(
2-ethylhexyl
) phtalhate, and acetylsalicylic acid resulted in differential increases of
CAT
protein 48 h after exposure. Nonsteroidal anti-inflammatory drugs including ibuprofen, fenbupen, naproxen, and acetaminophen also up-regulated ACOX::
CAT
. Phorbol 12-myristate 13-acetate, a nongenotoxic carcinogen that is not classified as a peroxisome proliferator, also resulted in a slight induction of ACOX::
CAT
, consistent with the role of cell proliferation in tumor progression. The carcinogenic compounds 4-nitroquinoline N-oxide, ethyl methanesulfonate, diethylstilbestrol, and 2-aminoanthracene did not induce ACOX::
CAT
. Although the significance of peroxisome proliferators and their impact on humans is still unknown, the ability to identify them is of interest to the pharmaceutical and chemical industries. This assay was able to detect known peroxisome proliferators tested in approximately 48 h of exposure and to distinguish them from genotoxic carcinogens.
...
PMID:Detection of peroxisome proliferators using a reporter construct derived from the rat acyl-CoA oxidase promoter in the rat liver cell line H-4-II-E. 910 62
