Role of Human Breast Cancer Related Protein versus P-Glycoprotein as an Efflux Transporter for Benzylpenicillin: Potential Importance at the Blood-Brain Barrier.
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.
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Yangfang
Y
Li
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Qian
Q
Wu
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, United States of America.
Chen
C
Li
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Ling
L
Liu
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Kun
K
Du
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Jin
J
Shen
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Yuqin
Y
Wu
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Xiaofen
X
Zhao
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Mei
M
Zhao
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Lingyun
L
Bao
Department of Neonate, Kunming Children's Hospital, Kunming, China.
Jin
J
Gao
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, United States of America.
Richard F
RF
Keep
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, United States of America.
Jianming
J
Xiang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010400:Penicillin G / Q000378:metabolism / Q000493:pharmacokinetics*; D015854:Up-Regulation
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000900:Anti-Bacterial Agents; D009363:Neoplasm Proteins; D010400:Penicillin G