UGT1A9 Genotype

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PackagingCharacterization ProvidedSafety, Handling, and Storage

They are high activity (*1/*1), reduced activity (*1/*3) and low activity (*3/*3). The low activity of the UGT1A9*3 allele appears to be substrate-dependent (see below).

UDP-glucuronosyltransferases (UGTs) catalyze glucuronidation of a variety of structurally dissimilar substrates, including drugs, endobiotics and carcinogens. UGT1A9 is abundant in the human liver where it can conjugate phenols, steroids, organic acids, anticancer drugs, and the procarcinogens present in tobacco (Girard et al., 2004). UGT1A9 has been identified as one of the enzymes responsible for glucuronidation of the active metabolite of irinotecan. Propofol serves as a UGT1A9 specific probe substrate (Court, 2005).

UGT1A9 is a polymorphically-expressed enzyme. Alleles UGT1A9*2 and UGT1A9*3 were identified at low frequency in African American and Caucasians, respectively, as summarized in the table below.

UGT1A9 Allele Frequency

 

Allele	African American	Asian	Caucasian	Hispanic
UGT1A9*1	0.975	---	0.964 – 0.978	---
UGT1A9*2	0.025	---	ND	---
UGT1A9*3	ND	---	0.006 – 0.036	---

--- = No Data Available
ND = Not detected

The amino acid change from cysteine to tyrosine (C3Y) in UGT1A9*2 is located in the signal peptide of the protein and should not affect its enzymatic activity. The UGT1A9*2 activity toward anticancer drug SN-38 and flavopiridol glucuronidation was not significantly different from the wild type (Villeneuve et al., 2003).

The nucleotide change defining the UGT1A9*3 allele (T98C) leads to a methionine to threonine change at the 33rd codon. The 33rd amino acid is located in or very near the active site of the enzyme and affects its activity toward some enzyme substrates. UGT1A9*3 expressed in HEK293 cells was associated with reduced intrinsic clearance of SN-38, 4-hydroxyestrone and 4-hydroxyestradiol (Villeneuve et al., 2003; Thibaudeau et al., 2006). The M33T amino acid change did not affect enzyme’s activity toward flavopiridol and increased activity of the UGT1A9*3 protein for a few other substrates of this isozyme (Guillemette and Villeneuve, 2003).

To the best of our knowledge, the UGT1A9 low activity microsomes represent the first human homozygous for UGT1A9*3 ever identified.

Packaging

Concentration: 20 mg/mL
Suspension buffer: 250 mM sucrose

Characterization Provided

• Genotype for UGT1A9
• Specific content of cytochrome P450
• Specific content of cytochrome b5
• NADPH-cytochrome c reductase activity
• CYP1A2 Phenacetin O-dealkylation
• CYP2A6 Coumarin 7-hydroxylation
• CYP2B6 Bupropion hydroxylation
• CYP2C8 Amodiaquine N-dealkylation
• CYP2C9 Diclofenac 4´-hydroxylation
• CYP2C19 S-Mephenytoin 4´-hydroxylation
• CYP2D6 Dextromethorphan O-demethylation
• CYP2E1 Chlorzoxazone 6-hydroxylation
• CYP3A4/5 Testosterone 6β-hydroxylation
• CYP3A4/5 Midazolam 1´-hydroxylation
• CYP4A11 Lauric acid 12-hydroxylation
• FMO Benzydamine N-oxidation
• UGT1A1 Glucuronidation of Estradiol
• UGT2B7 Glucuronidation of Morphine
• UGT1A6 Glucuronidation of Naphthol
• UGT1A9 Glucuronidation of Propofol
• UGT1A4 Glucuronidation of Trifluoperazine
• Donor information (age, ethnicity, gender, cause of death and infectious disease status)

Safety, Handling, and Storage

Informed Consent Statement

A single organization regulates and oversees the use of human tissue intended for transplantation in the United States, namely the United Network for Organ Sharing (UNOS). Organ donors may elect to have their organs used either for transplantation only, or for transplantation or research. Thus, the donor (or the donor's family) has the right to prevent the use of the donor's organs for research. Regardless of the use of donated organs, no compensation is given to the donor’s family; any such compensation is illegal in the United States. In those cases where donors (or family members) elect to withhold organs from research uses, any organs that cannot be transplanted are discarded.

XenoTech receives hepatic, renal, intestinal, pulmonary, and other human tissue from various regional organ procurement organizations (OPOs) that obtain organs approved for research use. Regulations in the United States require that, regardless whether the organ is intended for transplantation or research purposes, the organ donor's identity be treated as highly confidential information. Organ procurement organizations maintain the informed consent records from each donor, and our Standard Operating Procedure requires that XenoTech personnel confirm the existence of informed consent for research purposes, prior to transport of organs to XenoTech. This procedure is intended to ensure that XenoTech manufactures human-derived products only when informed consent has been granted for research use of those specific organs. XenoTech does not, and, in consideration of confidentiality, cannot obtain the informed consent records from these organizations.

All human tissue accepted by XenoTech has been tested for the possible presence of various infectious diseases, and XenoTech does not accept human-derived material unless the donor has tested negative (non-reactive) for RPR, HIVAb, HTLVAb, HBsAg and HCVAb. All human tissue is also tested for CMVAb.  However, due to the widespread (nearly ubiquitous) appearance of CMV in the population, and its relative insignificance as an infectious agent, tissues from donors reactive for CMVAb are accepted.  The serology status of each donor is typically determined by ELISA by the organ procurement hospital.

XenoTech does not deal directly with - nor does it make any direct payments to - the surgeons who procure organs or the medical institutions where they work.

Caution

In the case of human tissue, XenoTech accepts only non-transplantable tissue from donors who test negative for HIV 1 and 2, HTLV, and Hepatitis B and C. However, as a precaution, all human-de­rived samples should be regarded as a potential bio­hazard and should be stored, handled and discarded accordingly. Cellular and subcellular fractions are intended for in vitro use only.

Products

Product #	Name	Amount
HU1A9.HA	UGT1A9 High Activity (*1/*1)	0.5 mL at 20 mg/mL
HU1A9.MA	UGT1A9 Moderate Activity (*1/*3)	0.5 mL at 20 mg/mL
HU1A9.NA	UGT1A9 No Activity (*3/*3)	0.5 mL at 20 mg/mL