2(3)tert-Butyl4hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarolinhibited NAD(P)HL quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.21 activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones an may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protectie effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.The widely used antioxidant food additive 2(3)-tert-butyl-4-hydroxyanisole (BHA) has a number of interesting and potentially important pharmacological properties. BHA Administration of BHA to mice has little or no effect on numerous other monooxygenase activities of hepatic microsomes (11,15,17), although ring hydroxylation of aniline is markedly enhanced (11). Liver microsomes from BHA-fed mice also produce altered patterns of metabolites from benzo[a]pyrene in vitro. Lam and Wattenberg (18) observed decreased epoxidation and increased formation of 3-hydroxybenzo[a]pyrene relative to controls, and these changes were accompanied by a 50% decrease in the binding of metabolites to DNA (19,20).The NADH-and NADPH-linked quinone oxidoreductase here called quinone reductase has also been designated variously as menadione reductase, DT-diaphorase, NAD(P)H dehydrogenase, and vitamin K reductase (21). Recent studies have shown that rat liver cytosol azoreductase activity for methyl red also reflects the action of quinone reductase (22, 23). Unusual features of this flavoprotein enzyme include: (i) comparable reaction with NADH and NADPH (24-26); (ti) potent and specific inhibition, in competition with reduced nicotinamide nucleotides, by dicoumarol and related vitamin K antagonists (24, 27); (iii) reversible stimulation of activity of the soluble cytosolic quinone reductase by serum albumin, neutral phospholipids, and a number of detergents (24,26,27); and (iv) broad specificity for a variety of hydrophobic quinones, including benzoquinones, na...

An outbreak of respiratory syncytial virus (RSV) infection occurred among 31 patients in a marrow transplant center over a 13-week period beginning in January 1990. RSV infection was also documented in 35 family members and employees. Of 18 patients with pneumonia, 14 (78%) died. None of 13 with upper respiratory infection died. Preengraftment patients tended to develop pneumonia more frequently than did engrafted patients. Early administration of ribavirin may have had a beneficial effect in patients with pneumonia. Antigenic and genomic analysis of 14 available isolates suggested that at least four different viral strains were responsible for the outbreak. One group of patients and 1 employee in spatial proximity were infected with the same strain and likely acquired their infections nosocomially. RSV infection in marrow transplant patients is a serious and life-threatening infection with a high mortality rate once pneumonia develops.

Soluble, glutathione-stimulated A5-3-ketosteroid isomerase (EC 5.3.3.1) activity of human and rat liver resides in very basic proteins with molecular weights of about 45,000 which are present in high concentrations in these tissues. Physicochemical and immunological evidence is presented for the identity of the proteins responsible for this enzymatic activity with the glutathione S-transferases (RX:glutathione Rtransferase, EC 2.5.1.18) that conjugate glutathione with a variety of electrophilic compounds. In the rat, the steroid isomerase is associated principally with the major transferase (B), which is also known as ligandin, and has the versatility to bind various hydrophobic compounds such as bilirubin, corticosteroids, and metabolites of a number of carcinogens. Other rat liver glutathione S-transferase species are far less active in the steroid isomerization reaction. The A5-3-ketosteroid isomerase activity of human liver is more uniformly distributed among the five glutathione S-transferases that have been described. Steroid isomerization differs fundamentally from other reactions promoted by glutathione S-transferases in that glutathione is not consumed in the reaction. However, because the transferase enzymes promote nucleophilic attack by glutathione on a variety of largely foreign organic substrates, a similar mechanism may be involved in the isomerase reaction. A5-3-Ketosteroids are among the few known naturally occurring substrates for these enzymes.The capacity of various animal and microbial systems to promote the enzymatic conversion of A5-3-ketosteroids (I) to the corresponding a, (3-unsaturated M4-3-ketosteroids (II) was described just over 20 years ago (1, 2). Whereas the enzyme from Pseudomonas testosteroni, a A5-3-ketosteroid isomerase (steroid A-isomerase, 3-oxosteroid A4-A5-isomerase, EC 5.3.3.1) that does not appear to require small molecules for its activity, has been the subject of intensive study from both structural and mechanistic viewpoints (2), far less is known about the corresponding enzymes of animal origin. Recently, Benson and Talalay (3) reported that the cytosol fraction of the livers of a number of species contains A5-3-ketosteroid isomerase activity which is markedly and specifically stimulated by (reduced) glutathione. Partial purification of the rat liver A5-3-ketosteroid isomerase revealed that it was a very basic protein (pI ca. 10) of molecular weight 43,000-45,000 and that it appeared to constitute a substantial fraction of the total proteins of the liver cytosol.These attributes are also characteristic of a family of liver proteins, the glutathione S-transferases which, because of their great versatility of binding and catalytic functions, have been studied in numerous laboratories in the past decade. Indeed, Litwack, Ketterer, and Arias (4) came to the conclusion that the liver proteins which had been investigated independently in each of their laboratories for the ability to bind bilirubin and bromsulfophthalein (5), to bind an azocarcinogen, at least in ...

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GSH transferase isoenzymes of class Mu (two forms), class Pi (one form) and class Alpha (two forms) were purified from liver cytosols of female CD-1 mice pretreated with an anticarcinogenic inducer, 2(3)-t-butyl-4-hydroxyanisole. GSH transferases GT-8.7, GT-8.8a and GT-8.8b, GT-9.0, GT-9.3, GT-10.3 and GT-10.6 contained a minimum of six types of subunits distinguishable by structural, catalytic and immunological characteristics. H.p.l.c. analysis of the subunit compositions of affinity-purified GSH transferases from liver cytosols of induced and non-induced male and female CD-1 mice showed that two anticarcinogenic compounds, 2(3)-t-butyl-4-hydroxyanisole and bisethylxanthogen, differed markedly in their specificities as inducers of GSH transferase.

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