Aromatic Amines An Assessment of the Biological and Environmental Effects (1981) / Chapter Skim
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Metabolism of Aromatic Amines
Metabolism of Aromatic Amines
Pages 40-59
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From page 40... ...
For example, acetyl metabol ites are not formed in dogs. These results illustrate the cliff iculty of conducting studies of metabolism to delineate the best test species for evaluating a new compound when there is 1 ittle or no information concerning the identity of the metabolite responsible for toxic or pharmacologic effects.
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From page 41... ...
During phase I metabolism, one or more polar groups ~ such as hydroxyl ~ are introduced into the hydrophobic parent molecule, thus allowing a "handle" or position for the phase II conjugating enzymes (such as uridine diphosphoglucuronyl transferase) to attack .
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From page 42... ...
The cytochromes are characterized by their spectral absorption maximum, which occurs at 450 nm when they are associated with carbon monoxide in the ir reduced state. Recent efforts have successfully resolved and characterized multiple forms of the cytochrome, and the study of these isolated forms of cytochrome P-450 provides information regarding the properties of individual cytochromes and aids investigations concerned with regulating the occurrence of each cytochrome.
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From page 43... ...
Also, although the evidence is indirect, genetic studies in mice on the regulation of N-hydroxylation of AAP indicate that one or very few genes are responsible for the induction of the cytochrome P-450 form the t ca talyzes N-hydroxylation of AAF (Thorgeirsson et al., 1977~. The occur rence of each cytochrome is dependent on many factors, and the relet ive role of each cytochrome must be integrated with other processes occurring dur ing metabolism and carcinogenesis.
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From page 44... ...
Hydroxamic acids are quite stable, in contrast to the notor ious instability of arylhydroxylamines. At present, arylhydroxylamines are believed to be the proximal carcinogens in the induction of bladder cancer by 44
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From page 45... ...
GLUCURONIDATION Perhaps the most important detoxif ication process is con jugation of metabolites of aromatic amines with glucuronic acid. As far as is known, all species are capable of this metabolic reaction.
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From page 46... ...
glucose-l-phosphate + UTP _py__p__sphory~as~ UDP-glucose + pyrophosphate UDP-glucose + 2NAD+ + H 0 _______UD_G-_____ p_ + H + 2H 2 ~ehy~rogenast UD glucuronic acid 2NAD UDP-glucuronic acid + AT-OH _ -- -g -- -Ufe°nYi-+ Ar-O-glucuronic acid + ODP AT-OH = hydroxylated aromatic amine UTP = uridine triphosphate Glucuron idation occurs pr imar fly on hydroxyl groups, but may also occur with carboxyl and amine groups. The formation of highly acidic, labile N-glucuronides may or may not be enzymatic.
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From page 47... ...
The primary amine groups may also be directly conjugated, producing N-sulfate conjugates (sulfamates) that are readily hydrolyzed in weakly acidic solutions and by ubiquitous hydrolytic enzymes (sulfatases}.
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From page 48... ...
The metabolic reaction apparently occurs in the reticuloendothelial cells of the liver, but not in the parenchymal cells (Govier, 1965~. Mucosa of the spleen and intestines are also capable of acetylation (Mandel, 19711.
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From page 49... ...
in studies with isoniaz id. The active metabolite of the carcinogenic aromatic amines for the induction of bladder cancer appears to be the hydroxylamine; thus, acetylation appears to be protective.
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From page 50... ...
The induction of liver tumors in rats by primary aromatic amines has been associated with their conversion to reactive, toxic sulfate conjugates of their hydroxamic acid derivatives (Irving, 1977~. This pathway is apparently restricted to rat liver and is ineffective in the livers of female rats of some strains.
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From page 51... ...
N-formyl, N-acetyl, or N-propionyl der ivatives of N-hydroxy-2-aminoflurorene resulted in tumor induction that was greater than that of the N-acetyl derivative, which was also the most effective substrate with partially purified rat liver arylhydroxamic acid N,O-acyltransferase. A third type of ester if ication of N-oxidized derivatives has been repor ted in the act teat ion of 4-hydroxylaminoqu inol ine-N-oxide in incuba Lion s conta in ing ATP-ser ine a nd seryl-adenos inemonophosphate synthetase (Tada and Tada, 1976)
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From page 52... ...
A more recent war iation in this area has been the generation of reactive benzidine derivatives by an arachidonicacid-dependent, prostaglandin synthetase system obtained from rat kidney (T. Zenser, St.
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From page 53... ...
One-electron non-enzymatic and enzymatic oxidation products of various carcinogenic aromatic acethydroxamic acids. Biochim.
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From page 54... ...
1978. Free radicals and carcinogenesis: Some properties of the nitroxyl free radical products by covalent binding of 2-nitrosofluorene to unsaturated lipids of membranes.
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From page 55... ...
1979. Metabolic activation of arylhydroxamic acids by N-O~acyltransferase of rat mammary gland.
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From page 56... ...
Erdos, eds. Proceedings of the First International Pharmacology Meeting, Volume 6: Metabolic Factors Con trol 1 i ng Dur a t ion of Dr ug Act ion .
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From page 57... ...
1979a. The primary aromatic amines: m eir biological properties and structure-activity relationships.
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From page 58... ...
Origins of Human Cancer, Book B: Mechanisms of Carcinogenesis. Cold Spring Harbor Conferences on Cell Prol if Oration, Volume 4 .
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From page 59... ...
- Sushi - , ede. Funda~ntale in Cancer Preventions Proceedings of the 6th International Symposium on me Princess Taka~tsu Cancer Research Fund, Tokyo, 1975.
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