David Turgeon
Laval University
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Featured researches published by David Turgeon.
The Journal of Steroid Biochemistry and Molecular Biology | 1999
Dean W. Hum; Alain Bélanger; Éric Lévesque; Olivier Barbier; Martin Beaulieu; Caroline Albert; Michel Vallée; Chantal Guillemette; André Tchernof; David Turgeon; Stéphanie Dubois
In recent years, the enzymes which are involved in the formation of DHT in steroid target tissues have been well investigated, however, enzymes responsible for the catabolism and elimination of steroids in these tissues, in particular the uridine diphospho-glucuronosyltransferase (UGT) family of enzymes, have received much less attention. We have recently demonstrated that human and monkey are unique in having high plasma levels of C19 steroid glucuronides. These circulating conjugates have been proposed to reflect the peripheral conversion of adrenal and gonadal C19 steroids to potent androgens, especially DHT. In humans, the presence of steroid UGT activities is found in the liver and several extrahepatic tissues including the prostate, mammary gland and ovary. In addition, UGT activities were observed in breast and prostate tumor cell lines such as MCF-7 and LNCaP, respectively. In agreement with the presence of steroid conjugating enzymes in extrahepatic tissues, UGT cDNA clones, which encode steroid conjugating proteins, have been isolated from libraries constructed from human and monkey prostate mRNA. The presence of UGT transcripts and proteins in extrahepatic tissues in both species, as determined by Northern blot, ribonuclease protection, specific RT-PCR, in situ hybridization, Western blot and immunocytochemistry analysis, indicate the relevance of steroid glucuronidation in tissues other than the liver. Knowing that both the human prostate and the human prostate cancer LNCaP cell line express steroid metabolizing proteins, including UGT enzymes, regulation of UGT mRNA and protein levels, as well as promoter activity was studied in these cells. The results demonstrate a differential regulation between the two highly related isoforms UGT2B15 and UGT2B17, where only the expression of UGT2B17 was affected following treatments of LNCaP cells with androgens, growth factors or cytokines. Steroid conjugation by UGT enzymes is potentially involved in hormone inactivation in steroid target tissues, thus modifications in UGT expression levels may influence hormonal responses.
The Journal of Steroid Biochemistry and Molecular Biology | 1998
Alain Bélanger; Dean W. Hum; Martin Beaulieu; Éric Lévesque; Chantal Guillemette; André Tchernof; Guy Bélanger; David Turgeon; Stéphanie Dubois
Conjugation of compounds by glucuronidation is a pathway found in all vertebrates studied to date. Although, it is widely recognized that the liver is a major site of glucuronidation, it is now clear that extrahepatic tissues are also involved in the conjugation of compounds to which these tissues are exposed. High levels of androsterone glucuronide and androstane-3alpha,17beta-diol glucuronide found in the human prostate, breast cyst fluid and ovary follicular fluid suggest that glucuronidation of 5alpha-reduced C19 steroids occurs in these tissues. Recently, we have reported the tissue distribution of UGT2B15, which can conjugate steroids in several human extrahepatic steroid target tissues including the skin, breast and prostate. We have also isolated a new UGT2B cDNA encoding UGT2B17, that conjugates ADT which is the major 5alpha-reduced C19 steroid glucuronide in the circulation of humans. UGT2B17 is also widely distributed in several human steroid target tissues. This gene was mapped to human chromosome 4q13 and has an exon/intron structure similar to that of rat UGT2B1 and UGT2B2. Both UGT2B15 and UGT2B17, which are able to catalyze the glucuronidation of DHT, are expressed in LNCaP cells. Interestingly, glucuronidation of steroids is markedly regulated by several factors including androgens and growth factors. Treatment of LNCaP cells with dihydrotestosterone (DHT) and epidermal growth factor (EGF) caused a decrease of DHT glucuronidation and UGT2B mRNA levels. RNase protection assays showed a specific decrease of UGT2B17 transcript in LNCaP cells treated with DHT and EGF however, the level of UGT2B15 mRNA was not affected. As well, Western blot analysis demonstrated a diminution of UGT2B17 protein level in response to DHT and EGF. These results demonstrate a differential regulation of different isoforms of steroid conjugating UGTs present in human prostate LNCaP cells. In addition, UGT2B17 was shown to be more labile than UGT2B15 indicating that regulation of UGT2B17 expression would lead to a more rapid change in the level of glucuronidated steroids. Expression of exogenous UGT2B17 in LNCaP cells by gene transfer led to a significant decrease in the androgen response. This result indicates the ability of UGT enzymes to regulate the androgen response by conjugating androgens which abolishes their interaction with their receptor and facilitates their clearance from the cell. The glucuronidation of steroids by UGT enzymes is an important mechanism by which the levels of steroids is regulated in steroid target tissues.
Endocrinology | 1997
Chantal Guillemette; Éric Lévesque; Martin Beaulieu; David Turgeon; Dean W. Hum; Alain Bélanger
Although androgens are important regulators in the prostate, other effectors such as growth factors may also act to maintain normal function of the gland. Human prostate and human prostate cancer LNCaP cells express steroid conjugating uridine diphospho-glucuronosyltransferase (UGT) enzymes, and it was shown that the level of UGT activities and transcripts is down-regulated by androgens, especially dihydrotestosterone (DHT). In the present study, we examined the interaction between androgen, epidermal growth factor (EGF), and steroid UGT enzymes. The formation of DHT glucuronide (DHT-G) was inhibited by 47% when LNCaP cells were treated for 6 days with 10 ng/ml of EGF. Northern blot analysis also demonstrated a decrease in the steady-state level of UGT2B transcripts. Treatment with both DHT (0.5 nm) and EGF (10 ng/ml) caused a greater decrease of DHT glucuronidation and UGT2B messenger RNA levels than when the cells were treated with either compound alone. RNase protection assays showed that treatment wit...
Biochemical Journal | 2002
Caroline Girard; Olivier Barbier; David Turgeon; Alain Bélanger
The present study reports the genomic organization and the characterization of a novel cynomolgus monkey UDP-glucuronosyltransferase (UGT) enzyme, UGT2B30. UGT enzymes are microsomal proteins that catalyse the transfer of the glucuronosyl group from UDP-glucuronic acid (UDPGA) to a wide variety of lipophilic compounds, namely hormonal steroids. The 15 kb UGT2B30 gene amplified by PCR showed a genomic organization similar to those encoding UGT2B human enzymes. The cDNA encoding UGT2B30 was isolated from a cynomolgus monkey prostate cDNA library, and the deduced amino acid sequence showed an identity of 94% with UGT2B19, a monkey isoform previously characterized. Stable expression of UGT2B30 protein in human kidney 293 (HK293) cells was assessed by Western-blot analysis and its conjugating activity was screened using 39 potential substrates. The UGT2B30 enzyme is active on many compounds of different classes, including testosterone, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol, androsterone, oestradiol, tetrahydroaldosterone and tetrahydrocortisone, with glucuronidation efficiencies (V(max)/K(m) ratios) ranging from 0.6 to 8.8 microl x min(-1) x mg of protein(-1). Reverse-transcriptase-PCR analysis revealed that the UGT2B30 transcript is expressed in several tissues, including prostate, testis, mammary gland, kidney, adrenals and intestine. The relative activity of UGT2B30 in comparison with other simian UGT2B isoforms, as well as its large variety of substrates, strongly suggest that this enzyme is essential to inactivation of several steroids.
Endocrinology | 2001
David Turgeon; Jean-Sébastien Carrier; Éric Lévesque; Dean W. Hum; Alain Bélanger
Drug Metabolism and Disposition | 2000
Olivier Barbier; David Turgeon; Caroline Girard; Mitchell D. Green; Thomas R. Tephly; Dean W. Hum; Alain Bélanger
Journal of Molecular Biology | 2000
David Turgeon; Jean-Sébastien Carrier; Éric Lévesque; Barbara G. Beatty; Alain Bélanger; Dean W. Hum
Journal of Lipid Research | 2003
David Turgeon; Sarah Chouinard; Patrick Bélanger; Serge Picard; Jean-François Labbé; Pierre Borgeat; Alain Bélanger
Drug Metabolism and Disposition | 2003
David Turgeon; Jean-Sébastien Carrier; Sarah Chouinard; Alain Bélanger
Biochemical and Biophysical Research Communications | 2000
Jean-Sébastien Carrier; David Turgeon; Kim Journault; Dean W. Hum; Alain Bélanger