Metabolic activation of N-hydroxy arylamines, N-hydroxy heterocyclic amines and ring-hydroxymethyl polycyclic aromatic hydrocarbons by human sulfotransferases
Arylamines and polycyclic aromatic hydrocarbons (PAHs) are two major classes of chemical carcinogens. N-Hydroxylation of arylamines is regarded to be a necessary process for their mutagenicity and carcinogenicity, while alkyl-hydroxylation is the major metabolic pathway for alkyl-substituted PAHs. Evidence has been presented that sulfation of several N-hydroxy arylamines and hydroxymethyl PAHs is an important pathway leading to the formation of ultimate carcinogens in experiment animals. Sulfation of these chemicals forms putative sulfuric acid ester intermediates that can rearrange to electrophilic nitrenium or carbenium ions capable of forming covalent adducts with important cellular macromolecules. In order to study the metabolic activation by sulfotransferase(s) in various human tissue preparations an in vitro enzymatic assay was established. A metabolic phenotyping method was also developed for thermostable phenolsulfotransferase (TS-PST) in platelet homogenates (correlated with TS-PST activity in other tissues) based on a simple colorimetric assay using 2-naphthol as substrate. By using a PAPS-regenerating system to supply the activated sulfate and calf thymus DNA to trap the reactive metabolites, we found that N-hydroxy derivatives of the carcinogens, 4-aminobiphenyl (4-ABP), 4,4[prime]-methylene-bis(2-chloroaniline) (MOCA), 2-acetylaminofluorene (2-AAF), 2-aminofluorene (2-AF), 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), and 2-amino-6-methyldipyrido [1,2-1:3[prime],2[prime]-d]imidazole (Glu-P-1) were metabolically activated by human TS-PST. On the other hand, three methyl-hydroxylated derivatives (7-OH, 12-OH, and 7,12-diOH) of 7, 12-dimethylbenz[a]anthracene (DMBA) were metabolically activated by human steroid sulfotransferase. Human sulfotransferase(s)-mediated activation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was not observed.
- Research Organization:
- Arkansas Univ., Fayetteville, AR (United States)
- OSTI ID:
- 6755326
- Resource Relation:
- Other Information: Thesis (Ph.D.)
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
METABOLIC ACTIVATION
BIOLOGICAL PATHWAYS
ENZYME IMMUNOASSAY
POLYCYCLIC AROMATIC AMINES
CARCINOGENESIS
SULFATION
POLYCYCLIC AROMATIC HYDROCARBONS
ADDUCTS
CYTOCHEMISTRY
HYDROXYLATION
AMINES
AROMATICS
BIOASSAY
BIOCHEMISTRY
CHEMICAL REACTIONS
CHEMISTRY
HYDROCARBONS
IMMUNOASSAY
ORGANIC COMPOUNDS
PATHOGENESIS
560300* - Chemicals Metabolism & Toxicology
550200 - Biochemistry