POLYMORPHISMS OF DRUG TRANSPORTERS AND CLINICAL RELEVANCE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 626

TABLE 21.1. ( Continued )

Transporter Variant Function Substrates Refs.

P-gp N21D, F103L,

A998T

↔ Bisantrene, calcein-AM,

daunorubicin, bodipy-FL

9,10,80,81

S400N ↔ , ↓ forskolin, bodipy-FL

A893S ↔ , ↑ prazosin, bodipy-FL

verapamil, bodipy-FL
vinblastine, rhodamine 123,
vinblastine, vincristine,
doxorubicin, digoxin,
amprenavir, indinavir,
lopinavir, ritonavir,
saquinavir, calcein-AM,
cyclosporin A, verapamil

↔

MRP1 T73I, S92F,

T117M, R230Q,
R633Q, G671V,
R723Q,
C1047S,
R1058Q,
S1512L

Leukotriene C 4 , estradiol
17

84,85

-glucuronide, glutathione

R433S, A989T ↓ , ↔

MRP2 R412G, R1150H ↓ Methotrexate, glutathione- 90,91,93,94

V417I, A1450T ↔ methylfluorescein,

R768W, I1173F ↓ , ↓↓ 2,4-dinitrophenyl-S-

S789F ↑ glutathione, leukotriene C 4 ,

Q1382R ↓↓ estradiol 17 -glucuronide,

gluthothione-
monochlorobimane,
carboxyfluorescein

MXR V12M, Q141K ↓ , ↔ Mitoxantrone, topotecan, 97,175,176

A149P, R163K, ↔ doxorubicin, SN-38,

Q166E, P269S esterone 3-sulfate, DHEAS,

I206L ↑ PAH, bodipy FL-prazosin,

S441N, N590Y,
D620N

↓ pheophorbide a

BSEP E297G ↔ , ↓ Glycocholate, taurocholate 177,178

↓

R432T

↔

D482G

were tested functionally in heterologous expression systems with model substrates,
and 22 variants reduced function. Interestingly, those variants that were detrimental
to function were more likely to be amino acid changes at evolutionarily conserved
positions. Another intriguing result from this multitransporter analysis is that some
protein-altering variants can change substrate specificity. In a survey of nine SLC