Drug Transporters. Группа авторов

Скачать книгу

      3.3.2 Substrates

MATE proteins transport a wide array of chemicals (Tables 3.1 and 3.2). Medication substrates include antidiabetic drugs (metformin), antihistamines (cimetidine), antiarrhythmic drugs (procainamide), antivirals (acyclovir and ganciclovir), anticancer drugs (topotecan, imatinib), antibiotics (cephalexin) [12, 16, 27]. Endogenous molecules and nutrients transported by MATEs include creatinine, N ¹‐methyladenosine, N‐methyl nicotinamide (NMN), guanidine, and thiamine. Notably, not all of these molecules are cations with cephalexin being a zwitterion [16, 27]. Mice lacking Mate1 have elevated accumulation of cephalexin in their kidneys confirming it is a Mate substrate [28]. Likewise, anions such as estrone sulfate, acyclovir, and ganciclovir can also be transported by rMate1 [27]. Thus, while MATEs are often considered the major carriers of organic cations in the liver and kidneys, they are able to transport a wider range of substrates.

      While there is significant overlap in substrates between MATE1 and MATE2‐K, there are select compounds that are differentially transported by the two isoforms. For example, cephalexin and cephradine are transported by hMATE1, but not hMATE2 [27]. In addition, cimetidine has a greater affinity for rabbit Mate1 (denoted as rbMate1) compared with rbMate2‐K [20], whereas there is a high affinity for both hMATE1 and hMATE2‐K [29]. The opposite was observed for choline, which has greater affinity for rbMate2‐K [20].

TABLE 3.1 Prototypical and endogenous substrates of MATE transporters

Substrates	Isoforms	Transport kinetics	References
4‐(4‐(Dimethyl amino)styryl)‐N‐methylpyridinium iodide (ASP+)	hMATE1	K m = 3.2 ± 1.8 μM	[129]
	hMATE2‐K	K m = 5.4 ± 1.7 μM	[129]
Dopamine	hMATE1	K m = 0.56 ± 0.18 mM V max = 3.71 ± 0.15 nmol/mg protein/min	[51]
	hMATE2‐K	K m = 2.48 ± 0.65 mM V max = 7.69 ± 1.12 nmol/mg protein/min	[51]
	mMate1	K m = 0.53 ± 0.08 mM V max = 8.73 ± 0.08 nmol/mg protein/min	[51]
Estrone sulfate	hMATE1	K m = 0.47 ± 0.02 mM V max = 0.53 ± 0.06 nmol/mg protein/2 min	[27]
	hMATE2‐K	K m = 0.85 ± 0.17 mM V max = 0.85 ± 0.14 nmol/mg protein/2 min	[27]
Na‐methyladenosine	mMate1	K m = 246 ± 14 μM V max = 76.7 ± 3.0 pmol/mg protein/min	[50]
	hMATE2‐K	N.R.	[50]
1‐Methyl‐4‐phenylpyridinium (MPP+)	hMATE1	K m = 0.10 ± 0.02 mM V max = 1.47 ± 0.13 nmol/mg protein/2 min	[27]
		K m = 34.5 ± 12.9 μM	[59]
	hMATE2‐K	K m = 93.5 ± 4.9 μM	[6]
		K m = 0.11 ± 0.01 mM V max = 1.15 ± 0.09 nmol/mg protein/2 min	[27]
N‐methyl nicotinamide (NMN)	hMATE1	K m = 301 ± 18 μM	[102]
	hMATE2‐K	K m = 422 ± 63 μM	[102]
Tetraethylammonium (TEA)	hMATE1	K m = 0.38 ± 0.07 mM V max = 2.37 ± 0.23 nmol/mg protein/2 min	[27]
		K m = 0.58 ± 0.12 mM V max = 0.81 ± 0.09 nmol/mg protein/min	[67]
		K m = 366 ± 17 μM V max = 7.54 ± 0.21 nmol/min/mg protein	[29]
	hMATE2‐K	K m = 0.83 ± 0.15 mM	[6]
		K m = 0.76 ± 0.18 mM V max = 1.76 ± 0.25 nmol/mg protein/2 min	[27]
		K m = 375 ± 68 μM V max = 1.16 ± 0.14 nmol/min/mg protein	[29]
	rMate1	K m = 570 ± 64 μM	[16]
		K m = 260 ± 10 μM V max = 5.4 ± 0.2 nmol/min/mg protein	[17]
	rbMate1	K t = 160 ± 15 μM	[20]
	rbMate2‐K	K t = 77 ± 12 μM	[20]
	mMate2	K m = 710 μM V max = 400 pmol/min/mg protein	[22]

      ^a N.R.: not reported.

Through the use of double‐transfected cells expressing both hOCT1 and hOCT2 along with hMATE1, it is possible to investigate the role of hMATE1 in the apical efflux of chemicals [30]. In MDCK cells expressing both hOCT1/hMATE1, the transcellular transport (basolateral‐to‐apical) can be observed for TEA, MPP⁺, metformin, cimetidine, creatinine, guanidine, procainamide, and quinidine [31]. Largely similar results have been obtained for polarized MDCK cells containing hOCT2/hMATE1 [30, 31].

Скачать книгу