. 2011 Apr 1;4:11–33. doi: 10.2147/PGPM.S18861

Table 2.

Most common naturally occurring functional polymorphisms in major human Phase II drug-metabolizing enzymes: allele frequency, functional effect, and highlights of clinical relevance

Allelic variants	Polymorphism/substitution	Allele frequency (%)			Functional effect	Highlights of clinical relevance
Allelic variants	Polymorphism/substitution	Caucasian	Asian	African	Functional effect	Highlights of clinical relevance
*UGT1A1*^a						UGT1A1 low promoter activity alleles (eg, UGT1A1*28) is significantly associated with ↓ glucuronidation of SN-38 (the active metabolite of irinotecan), thereby resulting in ↑ risk for irinotecan-induced toxicity. Genetic variations in UGT1A1 may modify susceptibility to steroid-related cancers including breast, ovarian, endometrial and prostate cancers.
UGT1A16*	G71R	0	13–23	–	↓ Activity
UGT1A128*	(TA)6>(TA)7 in promoter	29–40	13–16	36–43	↓ Expression
UGT1A133*
UGT1A134*	(TA)6>(TA)5 in promoter	0.0–0.7	0	3–8	↑ Expression
	(TA)6>(TA)8 in promoter	0–0.7	0	0.9–7.0	↓ Expression
*UGT1A6*^a						UGT1A6 catalyses the glucuronidation of aspirin and acetaminophen. “Low activity” UGT1A6 variants, leading to increased salicylate levels in aspirin users, are associated with a lower risk of colon cancer.
UGT1A62*	T181A, R184S	30	23		↓ Activity
UGT1A63*	R184S	1–2	1.6		Unknown
UGT1A64*	T181A	2.4			Unknown
*UGT1A7*^a
UGT1A72*	N129K, R131K	24–34	15	39	Similar activity	UGT1A7 is an important extrahepatic UGT that inactivates a variety of carcinogenes. Low-activity UGT1A7 variants increases the risk of developing tobacco-related cancers, specifically orolaryngeal cancer.
UGT1A73*	N129K, R131K, W208R	23–36	26	23	↓ Activity
UGT1A74*	W208R	1–1.7	0	1	↓ Activity
*UGT2B7*^a						UGT2B7 is of major significance for the glucuronidation of a number of clinically important drugs (eg, morphinan derivatives, epiribicin, and zidovudine. Further studies are needed to elucidate the clinical impact of the UGT2B7 polymorphism.
UGT2B72*	H268Y	49–54	27		Similar or decreased activity
*UGT2B15*^a						UGT2B15 is the most efficient UGT2B involved in the inactivation of steroid hormones, mainly androgens. UGT2B15 polymorphisms have a potential role in a modified risk of prostate cancer.
UGT2B152*	D85Y	52–55	36–49	39	↑ Activity
*SULT1A1*^b						SULT1A1 is the most highly expressed hepatic SULT. SULT1A1 plays an important role in the sulfation of the metabolites of tamoxifen, 4-hydroxy-tamoxifen and endoxifen. SULT1A1*2 is associated with decreased survival of breast cancer patients treated with tamoxifen.
SULT1A12*	R213H	25–36	4.5–17.0	27–29	↓ Activity and ↓ thermal stability Similar activity
SULT1A13*	M223V	1.2	0.6	23	↓ Activity and ↓ thermal stability Similar activity
*GST*^c
GSTA1B*	Promoter point mutation (T-631G, T-567G, C-69T, G-52A)	40		41	↓ Expression	GSTA1 is involved in glutathione conjugation of the active metabolites of CPA. GSTA1B allele is associated with higher survival rate of breast cancer patients treated with CPA-containing chemotherapy. The GSTM null genotype is associated with an increased risk of the lung, colon, and bladder cancer. AML patients carrying GSTM0 appears to have a better response to adriamycin and cyclophosphamide treatment. The GSTP1B allele is associated with lower clearance of etoposide and reduced risk of relapse in childhood ALL patients. The GSTP1B allele is associated with increased survival rate in patients with advance colorectal cancer or breast cancer. The GSTT1 deletion is associated with reduced risk of relapse in childhood ALL patients. The GSTT1 deletion is a poor prognostic factor for survival in adult ALL.
GSTM10*	Gene deletion	42–58		27–41	Abolished activity
GSTP1B*	I105V	6–40		54	↓ Activity
GSTT10*	Gene deletion	2–42			Abolished activity
*NAT*^d						NAT114 and 17 are associated with slow acetylator phenotype. NAT25, 6, 7, 10, 14, and 19 lead to slow acetylator phenotype. NAT2 slow acetylator phenotype is associated with increased susceptibility to hydrolazine- and isoniazid-induced toxicity. NAT2 slow acetylator phenotype is associated with increased risk of bladder cancer.
NAT14*	Wild-type				Normal
NAT114*	R187Q	1.3–3.7			↓ Activity
NAT114*	R187Stop				↓ Activity
NAT117*	R64W				↓ Activity
NAT119*	R33Stop				↓ Activity
NAT122*	D251V				↓ Activity
NAT24*	Wild-type				Normal
NAT25*	I114T				↓ Activity
NAT26*	R197Q				↓ Activity
NAT27*	G286E				↓ Activity
NAT210*	E167K				↓ Activity
NAT214*	R64Q				↓ Activity
NAT217*	Q145P				↓ Activity
NAT219*	R64W				↓ Activity
*TPMT*^e						TPMT is involved in the methylation reaction of mercaptopurine, an anticancer drug used in the treatment of childhood ALL. The TPMT genotype correlated well with in-vivo enzyme activity and is clearly associated with a risk of mercaptopurine-induced toxicity. Patients with poor or intermediate TMPT activity may tolerate only one-tenth to half of the average mercaptopurine dose.
TPMT2*	A80P	0.0–0.5	0	0.0–0.4	↓ Activity
TPMT3A*	A154Y, Y240C	0.0–0.6	0–1	0.0–0.8	Abolished activity
TPMT3B*	Y240C	–	0	–	9-fold ↓ activity
TPMT3C*	A154Y	0.2–3.3	0.0–0.2	2.4–7.6	1.4-fold ↓ activity

Notes:

Data on UGT SNP allele frequencies, function effect, and clinical relevance are summarized from Guillemette⁶ and Nagar and Remmel;⁷

Data on SULT1A1 SNP allele frequencies, function effect, and clinical relevance are summarized from Glatt and Meinl⁸ and Nowell and Falany;⁹

Data on GST SNP allele frequencies, function effect, and clinical relevance are summarized from Lo and Ali-Osman¹⁰ and McIlwain;¹¹

Data on NAT SNP allele frequencies, function effect, and clinical relevance are summarized from Sim et al,¹³ Hein,¹⁵ and Agundez;¹³⁹

Data on TPMT SNP allele frequencies, function effects, and clinical relevance are summarized from Zhou¹⁸ and Hamdy et al.¹⁴⁰

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CPA, cyclophosphamide.