期刊
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 58
卷 58, 期 -, 页码 663-687出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010617-052713
关键词
homeostasis; drug transporter; drug metabolizing enzyme; OAT1; OAT3; OCT1; OCT2
资金
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD090259, P50HD090259] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK109392] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM104098] Funding Source: NIH RePORTER
- NICHD NIH HHS [U54 HD090259] Funding Source: Medline
- NIDDK NIH HHS [R01 DK109392] Funding Source: Medline
- NIGMS NIH HHS [R01 GM104098] Funding Source: Medline
The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN(organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) andOCT2(SLC22A2)-are widely studied drug transporters. Nevertheless, analyses of knockout mice and other data indicate that SLC22 transporters regulate key metabolic pathways and levels of signaling molecules (e.g., gut microbiome products, bile acids, tricarboxylic acid cycle intermediates, dietary flavonoids and other nutrients, prostaglandins, vitamins, short-chain fatty acids, urate, and ergothioneine), as well as uremic toxins associated with chronic kidney disease. Certain SLC22 transporters-such as URAT1 (SLC22A12) and OCTN2 (SLC22A5)-are mutated in inherited metabolic diseases. A new systems biology view of transporters is emerging. As proposed in the remote sensing and signaling hypothesis, SLC22 transporters, together with other SLC and ABC transporters, have key roles in interorgan and interorganism small-molecule communication and, together with the neuroendocrine, growth factor-cytokine, and other homeostatic systems, regulate local and whole-body homeostasis.
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