The separation and purification of rat liver UDP-glucuronyltransferase activities towards testosterone and oestrone

Weatherill, Philip J.; Burchell, Brian

doi:10.1042/bj1890377

Cited by 47 publications

(5 citation statements)

References 16 publications

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“…Further evidence from purification studies, however, has now established that multiple isoenzymes of UDP-glucuronyltransferase exist in rat liver, so that at least five such isoenzymes develop postnatally and are responsible for the group 2 activities (Burchell, 1980;Weatherill & Burchell, 1980;Falany & Tephly, 1983;von Meyerinck et al, 1985), whereas possibly only a single 'foetal' isoenzyme is responsible for all group 1 activities (Scragg et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Development of multiple activities of UDP-glucuronyltransferase in human liver

Leakey

Hume

Burchell

1987

Biochemical Journal

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UDP-glucuronyltransferase activities towards eight substrates were assayed in samples of foetal, term and adult human liver. Activities towards bilirubin, androsterone, testosterone, 1-naphthol, 4-nitrophenol and 2-aminophenol were present in foetal and term liver samples at less than 14% of adult values, whereas activity towards 5-hydroxytryptamine was present in foetal and term liver at 109 and 121% of adult values respectively. Thus a 'foetal' form of UDP-glucuronyltransferase may exist in human liver that is more restricted in substrate specificity than are those of the rat or rhesus monkey.

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Section: Introductionmentioning

confidence: 99%

Development of multiple activities of UDP-glucuronyltransferase in human liver

Leakey

Hume

Burchell

1987

Biochemical Journal

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“…The enzymes catalyze the transfer of the glucuronosyl group of UDP-glucuronate to a variety of structurally diverse nucleophiles. Though much of the broad substrate selectivity of the microsomal enzyme system is attributed to the presence of multiple enzyme forms (Burchell, 1980; Weatherill & Burchell, 1980;Matern et al, 1982;Owens & Mackenzie, 1982), enzyme preparations that are apparently homogeneous also exhibit a rather low degree of substrate selectivity (Magdalow et al, 1982;Matern et al, 1982), a property not uncommon to enzymes catalyzing detoxication reactions. Methods that probe the factors controlling the substrate selectivity of the enzymes are of considerable value in understanding the role of glucuronidation in the metabolism of xenobiotics.…”

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confidence: 99%

Stereoselectivity and regioselectivity of uridine 5'-diphosphoglucuronosyltransferase toward vicinal dihydrodiols of polycyclic aromatic hydrocarbons

Lewis¹,

Armstrong²

1983

Biochemistry

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The ability of a purified rat liver microsomal uridine-5'-diphosphoglucuronosyltransferase to catalyze the glucuronidation of stereoisomeric trans- and cis-9, 10-dihydroxy-9, 10-dihydrophenanthrenes and 4, 5-dihydroxy-4,5-dihydrobenzo[alpha]pyrenes is examined. The enzyme shows the ability to discriminate kinetically between the antipodes of trans-9, 10-dihydroxy-9, 10-dihydrophenanthrene with turnover numbers of 0.070 and 1.4 s-1 and kc/Kmapp values of 4.4 X 10(3) and 1.1 X 10(3) M-1 s-1 for the 9R, 10R and 9S, 10S stereoisomers. Glucuronidation of the nondissymmetric cis-9, 10-dihydroxy-9, 10-dihydrophenanthrene proceeds with a turnover number of 0.037 s-1 and kc/Kmapp of 18 X 10(3) M-1 s-1 to give a 60/40 mixture of the two possible diastereomeric products. Three of the four stereoisomers of 4,5-dihydroxy-4,5-dihydrobenzo[alpha] pyrene are regioselectively glucuronidated by the enzyme with a high degree of kinetic discrimination. Turnover numbers for the 4S,5S, 4R,5R, and 4S,5R stereoisomers are 4.1, 0.37, and 0.23 s-1 with kc/Kmapp values of 23.8 X 10(3), 0.23 X 10(3), and 3.15 X 10(3) M-1 s-1, respectively. The 4R,5S cis isomer is not a substrate. Enzyme-catalyzed reactions of the 4S,5S and 4S,5R isomers give exclusively (greater than or equal to 95%) the 4-glucuronide with the 4R,5R isomer giving the 5-glucuronide. The kinetic and regiochemical results indicate that the enzyme recognizes hydroxyl groups on the beta-face or bottom face of the 4,5-dihydroxy-4,5-dihydrobenzo[alpha]pyrenes.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…By the early 1980s it was clear that a number of hepatic microsomal UDPGTs existed in rabbits and rats. Reports from our laboratory, Bock and his colleagues (21)(22)(23), and Burchell's laboratory (24) led to this inescapable conclusion. However, evidence that rat hepatic microsomal UDPGTs could be isolated to homogeneity was still of major concern.…”

Section: Introductionmentioning

confidence: 94%

Isolation and purification of UDP-glucuronosyltransferases

Tephly¹

1990

Chem. Res. Toxicol.

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UDPGTs are members of a class of enzymes located in the endoplasmic reticulum and are encoded by a multigene family. These proteins are responsible for the glucuronidation of hundreds of xenobiotics of many chemical classes and many endogenous substances such as steroid hormones, bile acids, and bilirubin. There are a number of UDPGTs which have been identified by purification and characterization studies and a significant number which have been characterized by expression of cDNAs. On the basis of the primary structures elucidated they appear to have marked similarities (5) and are highly conserved. However, key differences in their functional properties appear to depend primarily on differences in amino acid sequences at or about the NH2-terminal area of the protein (5). Many of the UDPGTs have an extraordinarily broad substrate specificity; a few, however, are relatively specific for a given class of substrate (morphine, DT-1 UDPGTs). This places a burden on investigators to clearly identify which substrate and how many UDPGTs will be involved in any analysis of rates of glucuronidation in microsomal preparations. Caution should also be advised for extrapolation of data from hepatic microsomes of experimental animals to human hepatic microsomal preparations because human liver microsomes possess UDPGTs which are qualitatively different and, in certain cases, UDPGTs are present in human liver which are not present in lower animals.

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The separation and purification of rat liver UDP-glucuronyltransferase activities towards testosterone and oestrone

Cited by 47 publications

References 16 publications

Development of multiple activities of UDP-glucuronyltransferase in human liver

Development of multiple activities of UDP-glucuronyltransferase in human liver

Stereoselectivity and regioselectivity of uridine 5'-diphosphoglucuronosyltransferase toward vicinal dihydrodiols of polycyclic aromatic hydrocarbons

Isolation and purification of UDP-glucuronosyltransferases

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