Role of Human Breast Cancer Related Protein versus P-Glycoprotein as an Efflux Transporter for Benzylpenicillin: Potential Importance at the Blood-Brain Barrier

• Published in: PloS one Vol. 11; no. 6; p. e0157576
• Main Authors: Li, Yangfang, Wu, Qian, Li, Chen, Liu, Ling, Du, Kun, Shen, Jin, Wu, Yuqin, Zhao, Xiaofen, Zhao, Mei, Bao, Lingyun, Gao, Jin, Keep, Richard F, Xiang, Jianming
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2016; Public Library of Science (PLoS)
• Subjects: Access control; Animals; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacokinetics; Antibiotics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Benzylpenicillin; Biology and Life Sciences; Blood-brain barrier; Blood-Brain Barrier - metabolism; Breast cancer; Cancer; Cell culture; Central nervous system; Dogs; Drug resistance; Drug therapy; Drugs; Efflux; Engineering and Technology; Fluctuations; Flux; Glycoproteins; Humans; Madin Darby Canine Kidney Cells; Medical research; Medicine and Health Sciences; Metabolism; Metabolites; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neurosurgery; P-Glycoprotein; Penicillin G - metabolism; Penicillin G - pharmacokinetics; Pharmacology; Protein transport; Proteins; Research and Analysis Methods; Solutes; Substrate inhibition; Substrates; Toxic substances; Transport; Up-Regulation; Netherlands; Ann Arbor Michigan; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0157576

While the blood-brain barrier (BBB) protects the brain by controlling the access of solutes and toxic substances to brain, it also limits drug entry to treat central nervous system disorders. Many drugs are substrates for ATP-binding cassette (ABC) transporters at the BBB that limit their entry into the brain. The role of those transporters in limiting the entry of the widely prescribed therapeutic, benzylpenicillin, has produced conflicting results. This study investigated the possible potential involvement of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), two ABC transporters, in benzylpenicillin transport at BBB in human using MDCKII cells overexpressing those transporters as well as pharmacological inhibition. MDCKII cells overexpressing human BCRP (MDCKII-BCRP) but not those overexpressing human P-gp (MDCKII-MDR cells) had reduced [3H]benzylpenicillin uptake. Similarly, inhibiting BCRP increased [3H]benzylpenicillin uptake in MDCKII-BCRP cells, while inhibiting P-gp in MDCKII-MDR cells had no effect on uptake although there was evidence that benzylpenicillin is a substrate for canine P-gp. While inhibiting BCRP affected [3H]benzylpenicillin cell concentrations it did not affect transepithelial flux in MDCKII-BCRP cells. In summary, the results indicate that human BCRP and not human P-gp is involved in benzylpenicillin transport. However, targeting BCRP alone was not sufficient to alter transepithelial flux in MDCKII cells. Whether it would be sufficient to alter blood-to-brain flux at the human BBB remains to be investigated.