Human UGT1A8 and UGT1A10 mRNA Are Expressed In Primary Human Hepatocytes

Li, Xin; Bratton, Stacie M.; Radominska‐Pandya, Anna

doi:10.2133/dmpk.22.152

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…In the same tissues, we also analyzed the expression pattern of UGT1A9, an enzyme that is highly homologous to UGT1A10 in its nucleotides and amino acid sequence, but differs from it markedly in tissue distribution. Results presented in Table 2 confirm the previous findings of Li et al (2007) that although UGT1A10 is largely an extrahepatic enzyme, this UGT is also expressed in the liver at a very low level. Nonetheless, UGT1A10 is expressed mainly in the intestine FIG.…”

Section: Itä Aho Et Alsupporting

confidence: 88%

“…Because UGT1A10 seemed to be the most active human enzyme in dopamine glucuronidation, we evaluated the tissue specificity of expression of this isoform. Although studies with some tissues were done previously, there were inconsistencies in results, particularly regarding whether this enzyme is expressed in liver (Strassburg et al, 1997(Strassburg et al, , 1998(Strassburg et al, , 1999Mojarrabi and Mackenzie, 1998;Cheng et al, 1999;Zheng et al, 2002;Li et al, 2007;Nakamura et al, 2008). In addition, because dopamine is an important neurotransmitter in the brain, we wanted to find out whether UGT1A10 is expressed in the brain.…”

Section: Itä Aho Et Almentioning

confidence: 99%

“…UGT1A10 was considered an extrahepatic UGT that is mainly expressed in the intestine (Strassburg et al, 1997(Strassburg et al, , 1998(Strassburg et al, , 1999Mojarrabi and Mackenzie, 1998;Cheng et al, 1999;Zheng et al, 2002). However, in a recent study, low expression levels of UGT1A10 were detected in liver and hepatocytes (Li et al, 2007;Nakamura et al, 2008). Based on the latter, it might be speculated that low expression levels of UGT1A10 that were not detected previously could also occur in the brain.…”

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confidence: 99%

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Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Itäaho¹,

Court²,

Uutela³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The purpose of this work was to identify human UDP-glucuronosyltransferases (UGTs) capable of glucuronidating dopamine. Using a sensitive liquid chromatography-tandem mass spectrometry method, we screened all 19 known human UGTs and found that only one enzyme, UGT1A10, catalyzed dopamine glucuronidation at substantial rates, yielding both dopamine-4-O-glucuronide (37.1 pmol/min/mg) and dopamine-3-O-glucuronide (32.7 pmol/min/ mg). Much lower (<2 pmol/min/mg) or no dopamine glucuronidation activity was found for all other UGTs tested at 1 mM dopamine. Evaluation of the UGT1A10 expression pattern in human tissues by quantitative reverse transcription-polymerase chain reaction confirmed that it is mainly expressed in small intestine, colon, and adipose tissue, whereas only low levels were found in trachea, stomach, liver, testis, and prostate but not in brain. Dopamine glucuronidation assays using microsomes from human liver and intestine corroborated these findings because activity in intestinal microsomes was markedly higher than that in liver microsomes. Moreover, the glucuronidation regioselectivity in intestinal microsomes was similar to that of recombinant UGT1A10, and both enzyme sources exhibited sigmoidal kinetics with substrate affinity (K A ) values in the range of 2 to 3 mM. Examination of four UGT1A10 mutants, F90A, F90L, F93A, and F93L, revealed lower dopamine glucuronidation in all of them, particularly in F90A and F93A. Nonetheless, the substrate affinities of the four mutants were similar to that of UGT1A10. It is interesting to note that mutant F93L exhibited regioselectivity, conjugating dopamine at the 4-hydroxyl (OH) position approximately 3 times more efficiently than at the 3-OH position. These results shed new light on the structure and function of UGT1A10 and indicate that dopamine may be a useful probe substrate for this enzyme.

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Section: Itä Aho Et Alsupporting

confidence: 88%

Section: Itä Aho Et Almentioning

confidence: 99%

mentioning

confidence: 99%

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Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Itäaho¹,

Court²,

Uutela³

et al. 2008

Drug Metab Dispos

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“…The UGTs enzymes are membrane-bound and implicate in the biotransformation of important endogenous compounds as well as drugs and xenobiotics [13]. UGT-glucuronosyltransferase 1A8 is known as an enzyme in human body which is encoded by the UGT1A8 gene and belongs to the UGTs and express in extra-hepatic tissues.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Study on Similarity Effect of Thymoquinone on Epithelial Breast Cancer and Colorectal Cancer Cell Lines

Motaghed¹

2015

AJLS

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Abstract:Adenocarcinoma is known as a common type of cancer which includes 85% of breast carcinoma and 95% of colorectal carcinoma. Up until now, the cytotoxic effect of Thymoquinone on different types of tumor cells has been reported. It was hypothesized that Thymoquinone has similar effect on cancer arising from epithelial cells through gene expression analysis in MCF7 breast cancer and HT-29 colon cancer cell lines. The quantity and quality of RNA samples were identified using RNeasyPlus Mini kit and RNA 6000 Nano LabChip kit, respectively. The purified RNA samples of MCF7 cells were used in two-color 8×60K cDNA array platform with SurePrint Agilent technology. The hybridized cRNA/cDNA probes were identified due to labeling with red and green cyanine dyes using GE X hybridization buffer HI-RPM. LOWESS normalization reduced the dye bias on the array slide using feature extraction software. Gene ontology analysis was done after performing different steps of filtering to reduce not satisfied genes using Gene Spring software. Two-step RT-qPCR assay using Taq Man fast advanced master mix analyzed the most up and down regulated genes in MCF7 compared to HT-29 cancer cell lines. The 10 different cancer cell lines in a form of universal reference RNA was used as standard data set comparison and as a positive control RNA in cDNA array and RT-qPCR assay, respectively. The T-test statistical analysis of independent samples showed that there is no significant difference between two types of cell lines due to Thymoquinone treatment with p-value 0.844. Among the selected genes; CARD16, UGT1A8, SLC7A11, IFIT1, IF16 and IFIT3 were expressed significantly (0.009, 0.0001, 0.037, 0.098, 0.0001 and 0.033, respectively) in breast cancer compare to colon cancer cells. The findings indicated similar effect of Thymoquinone on cancer arising from epithelial cells.

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“…UGT1A9 is the primary enzyme and is expressed predominantly in liver and kidneys and, to a lesser extent, in the gastrointestinal tract. UGT1A8 and 1A10 are expressed throughout the gastrointestinal tract [69]. In vitro studies have shown that polymorphisms in the UGT1A9 gene result in significant alteration of the UGT enzymatic activity.…”

Section: Mycophenolic Acid (Mpa)mentioning

confidence: 99%

Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients

Zaza

Granata

Sallustio

et al. 2009

Clinical and Experimental Immunology

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SummaryAlthough notable progress has been made in the therapeutic management of patients with chronic kidney disease in both conservative and renal replacement treatments (dialysis and transplantation), the occurrence of medication-related problems (lack of efficacy, adverse drug reactions) still represents a key clinical issue. Recent evidence suggests that adverse drug reactions are major causes of death and hospital admission in Europe and the United States. The reasons for these conditions are represented by environmental/non-genetic and genetic factors responsible for the great inter-patient variability in drugs metabolism, disposition and therapeutic targets. Over the years several genetic settings have been linked, using pharmacogenetic approaches, to the effects and toxicity of many agents used in clinical nephrology. However, these strategies, analysing single gene or candidate pathways, do not represent the gold standard, being the overall pharmacological effects of medications and not typically monogenic traits. Therefore, to identify multi-genetic influence on drug response, researchers and clinicians from different fields of medicine and pharmacology have started to perform pharmacogenomic studies employing innovative whole genomic high-throughput technologies. However, to date, only few pharmacogenomics reports have been published in nephrology underlying the need to enhance the number of projects and to increase the research budget for this important research field. In the future we would expect that, applying the knowledge about an individual's inherited response to drugs, nephrologists will be able to prescribe medications based on each person's genetic make-up, to monitor carefully the efficacy/toxicity of a given drug and to modify the dosage or number of medications to obtain predefined clinical outcomes.

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Human UGT1A8 and UGT1A10 mRNA Are Expressed In Primary Human Hepatocytes

Cited by 15 publications

References 31 publications

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Gene Expression Study on Similarity Effect of Thymoquinone on Epithelial Breast Cancer and Colorectal Cancer Cell Lines

Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients

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