Evidence for a role of tert-butyl hydroxylation in the induction of pneumotoxicity in mice by butylated hydroxytoluene

Malkinson, Alvin M.; Thaete, Larry G.; Blumenthal, Elliott; Thompson, John A.

doi:10.1016/0041-008x(89)90269-x

Cited by 35 publications

(21 citation statements)

References 24 publications

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“…2‐stage carcinogenesis consists of initiation by the tobacco carcinogen, MCA, followed by promotion of the growth of initiated cells by BHT. BHT undergoes extensive pulmonary metabolism in mice to generate highly reactive oxidative species that cause a reversible pneumotoxicity consisting of peripheral epithelial cell damage, regenerative growth, and inflammation; these properties promote tumor growth in some mouse strains including BALB when BHT is administered after a carcinogen [19,20,22–25]. This experimental model affords the opportunity to compare hnRNP A1 and ASF/SF2 expression during early neoplasia after 2‐stage carcinogenesis (MCA + BHT) with the nonneoplastic proliferation that follows BHT treatment alone.…”

Section: Resultsmentioning

confidence: 99%

Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: Implications for pre‐mRNA processing

Zerbe

Pino

Pı́o

et al. 2004

Molecular Carcinogenesis

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Pre-mRNA processing is an important mechanism for globally modifying cellular protein composition during tumorigenesis. To understand this process during lung cancer, expression of two key pre-mRNA alternative splicing factors was compared in a mouse model of early lung carcinogenesis and during regenerative growth following reversible lung injury. Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and alternative splicing factor/ splicing factor 2 (ASF/SF2) act antagonistically to modulate splice site selection. Both hnRNP A1 and ASF/SF2 contents rose in adenomas and during injury-induced hyperplasia compared to control lungs, as measured by immunoblotting. While both proteins increased similarly during compensatory hyperplasia, hnRNP A1 increased to a much greater extent than ASF/SF2 in tumors, resulting in a 6-fold increase of the hnRNP A1 to ASF/SF2 ratio. Immunohistochemical analysis showed that hnRNP A1 localized exclusively within tumor nuclei, while ASF/SF2 appeared in cytoplasm and/or nuclei, depending on the growth pattern of the tumor cells. We also demonstrated cancer-associated changes in the pre-mRNA alternative splicing of CD44, a membrane glycoprotein involved in cell-cell and cell-extracellular matrix interactions. hnRNP A1 and ASF/SF2 expression is thus differentially altered in neoplastic lung cells by mechanisms that do not strictly arise from increased cell division. These changes are influenced by tumor histology and may be associated with production of variant CD44 mRNA isoforms. ß 2004 Wiley-Liss, Inc.

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Section: Resultsmentioning

confidence: 99%

Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: Implications for pre‐mRNA processing

Zerbe

Pino

Pı́o

et al. 2004

Molecular Carcinogenesis

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“…There is growing evidence that the metabolites BHT-BuOH and the corresponding quinone methide are more potent pneumotoxins than BHT per se (44,45). In vitro data suggest that putative toxic metabolites are formed readily in Clara cells (46), which are sites of high expression for cytochrome P450 enzymes.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 is essential for protection against acute pulmonary injury in mice

Chan

Kan²

1999

Proc. Natl. Acad. Sci. U.S.A.

540

333

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Nrf2 is a member of the ''cap 'n' collar'' family of transcription factors. These transcription factors bind to the NF-E2 binding sites (GCTGAGTCA) that are essential for the regulation of erythroidspecific genes. Nrf2 is expressed in a wide range of tissues, many of which are sites of expression for phase 2 detoxification genes. Nrf2 ؊͞؊ mice are viable and have a normal phenotype under normal laboratory conditions. The NF-E2 binding site is a subset of the antioxidant response elements that have the sequence GC-NNNGTCA. The antioxidant response elements are regulatory sequences found on promoters of several phase 2 detoxification genes that are inducible by xenobiotics and antioxidants. We report here that Nrf2 ؊͞؊ mice are extremely susceptible to the administration of the antioxidant butylated hydroxytoluene. With doses of butylated hydroxytoluene that are tolerated by wild-type mice, the Nrf2 ؊͞؊ mice succumb from acute respiratory distress syndrome. Gene expression studies show that the expression of several detoxification enzymes is altered in the Nrf2 ؊͞؊ mice. The Nrf2 ؊͞؊ mice may prove to be a good in vivo model for toxicological studies. As oxidative damage causes DNA breakage, these mice may also be useful for testing carcinogenic agents.butylated hydroxytoluene ͉ butylated hydroxyanisole ͉ antioxidant response element ͉ gene knockout ͉ acute respiratory distress syndrome T he study of human ␤-globin gene expression identified a number of regulatory DNA sequences found at the globin gene promoters and the locus control region (1-3). One of these sequences is the NFE2-AP1 motif that has the sequence of GCTGAGTCATGATGAGTCA (4-6). This sequence plays an important part in regulating globin gene expression as determined by in vitro and in vivo experiments (4,5,7,8).Three transcription factors, p45-Nfe2, Nrf1, and Nrf2, have been found to bind to this motif (9-13). These three proteins are members of the "cap 'n' collar" (CNC) subfamily of basic region-leucine zipper transcription factors. CNC is a homeotic gene required for the development of the head and neck structures in Drosophila (14). These CNC proteins have been shown to heterodimerize with another family of basic regionleucine zipper proteins, the p18-Mafs (15-18). A fourth member of this CNC subfamily recently has been cloned by sequence homology (19). Of these four CNC genes, only p45-Nfe2 is hematopoietic specific; the other three are ubiquitously expressed. Targeted disruption of p45-Nfe2, Nrf1, and Nrf2 was carried out to determine their function. Disruption of p45-Nfe2 results in a defect in megakaryocyte maturation with minimal effect on globin gene expression (20,21). Loss of Nrf1 results in embryonic lethality (22, 23), whereas Nrf2 Ϫ͞Ϫ mice are viable and show no obvious phenotype when cared for in a normal laboratory setting (24-26).The AP1-NFE2 motif was later found to be a subset of the antioxidant response element (27-30). Nrf1 and Nrf2 have been shown to transactivate reporter genes linked to the antioxidant response element (31, 3...

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“…One paper (Malkinson et al, 1989) offers an explanation for BHT-induced pulmonary toxicity in all inbred strains of mice but not in rats. One paper (Malkinson et al, 1989) offers an explanation for BHT-induced pulmonary toxicity in all inbred strains of mice but not in rats.…”

Section: Mechanistic Studiesmentioning

confidence: 99%

Scientific Opinion on the re‐evaluation of butylated hydroxytoluene BHT (E 321) as a food additive

2012

EFS2

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The Panel on Food Additives and Nutrient Sources added to Food (ANS) delivers an opinion reevaluating the safety of butylated hydroxytoluene (BHT) (E 321). BHT is an authorised synthetic antioxidant that was previously evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the latest in 1996 and the EU Scientific Committee for Food (SCF) in 1987. The SCF established an ADI of 0-0.05 mg/kg bw/day based on thyroid, reproduction and haematological effects in the rat. JECFA allocated an ADI of 0-0.3 mg/kg bw/day for BHT based on effects in the reproduction segments and hepatic enzyme induction seen in two separate 2-generation studies in rats. The Panel concluded that BHT is not of concern with respect to genotoxicity and that any carcinogenicity would be thresholded. After the last SCF evaluation, two new 2-generation studies have been reported which were the basis for the ADI set by JECFA. Both studies revealed a NOAEL of 25 mg/kg bw/day. Overall, the Panel concluded that the present database gives reason to revise the ADI of 0.05 mg/kg bw/day. Based on the NOAEL of 25 mg/kg bw/day and an uncertainty factor of 100, the Panel derived an ADI of 0.25 mg/kg bw/day. Since the NOAEL of 25 mg/kg bw/day is below the BMDL10 value of 247 mg/kg bw/day derived from the data for the incidence of hepatocellular carcinomas in male rats, the Panel concluded that this NOAEL also covers the hepatocellular carcinomas observed in the long-term studies with BHT. Exposure of adults to BHT is unlikely to exceed the newly derived ADI at the mean and at the 95th percentile. For exposure of children to BHT from its use as food additive, the Panel noted that it is also unlikely that this ADI is exceeded at the mean, but is exceeded for some European countries (Finland, The Netherlands) at the 95th percentile. SUMMARYFollowing a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on the re-evaluation of butylated hydroxytoluene (BHT) (E 321) as a food additive.BHT (E 321) is a synthetic antioxidant authorised as a food additive in the EU that was previously evaluated by the EU Scientific Committee for Food (SCF) in 1987 and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) several times, the latest in 1996.The SCF established an ADI of 0-0.05 mg/kg bw/day based on thyroid, reproduction and haematological effects in the rat. At its last evaluation JECFA allocated an ADI of 0-0.3 mg/kg bw/day for BHT, based on effects in the reproduction segments and hepatic enzyme induction, seen in two separate 2-generation studies in rats. These studies were probably not available at the time of the SCF evaluation.Specifications have been defined in the EU legislation Directive 2008/48/EC and by JECFA (JECFA, 2006). The purity is specified to be not less than 99%.Absorption, distribution, metabolism and excretion of BHT have been studied in mice, rats, rabbits, chickens, monkeys and humans. Overall, these studies show that BHT is r...

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Evidence for a role of tert-butyl hydroxylation in the induction of pneumotoxicity in mice by butylated hydroxytoluene

Cited by 35 publications

References 24 publications

Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: Implications for pre‐mRNA processing

Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: Implications for pre‐mRNA processing

Nrf2 is essential for protection against acute pulmonary injury in mice

Scientific Opinion on the re‐evaluation of butylated hydroxytoluene BHT (E 321) as a food additive

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