Читать книгу Transporters and Drug-Metabolizing Enzymes in Drug Toxicity - Albert P. Li - Страница 33

Hepatic transporter proteins facilitate drug metabolism and elimination by regulating the movement of drugs across hepatocyte cell membranes. They also are essential in maintaining bile acid homeostasis. Drug–drug interactions and genetic variants that impair the function of hepatic drug transporters can result in bile acid accumulation, which can lead to toxicity and DILI.

Hepatic transporters are generally described as influx or efflux transporters (Figure 2.4). Influx transporters located on the basolateral membrane of hepatocytes remove drugs and other compounds from blood in the liver sinusoidal space and transport into hepatocytes. Influx transporters include members of the solute carrier (SLC) superfamily, such as the sodium‐independent organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs), the organic cation transporters (OCTs), and the sodium‐dependent sodium taurocholate cotransporting polypeptide (NTCP) transporter. The OATP transporters OATP1B1 (SLCO1B1), OATP1B3 (SLCO1B3), and OATP2B1 (SLCO2B1) are most abundant in the liver [22] and are responsible for the uptake of many endogenous compounds, as well as statins, methotrexate, fexofenadine, bosentan, and rifampicin, among other drugs. OATP1B1 and OAT1B3 are also involved in bilirubin and bile acid uptake; however, the NTCP is primarily responsible for bile acid uptake. The OATP transporters are associated with various drug–drug interactions; for example, OATP1B1 and OATP1B3 are inhibited by atazanavir and ritonavir, cyclosporine, and gemfibrozil [23], and OATP1B1 is inhibited by the tyrosine kinase inhibitors pazopanib and nilotinib [24]. Drugs such as cyclosporin and rifampin that inhibit both OATP1B1 and OATP1B3 disrupt bilirubin uptake and can cause hyperbilirubinemia [25, 26]. Rotor type hyperbilirubinemia occurs when genetic mutations render both OATP1B1 and OATP1B3 deficient, thereby inhibiting bilirubin uptake [27].

Figure 2.4 Hepatic proteins involved in drug, bilirubin, and bile acid transport. Drugs are removed from the blood by influx transporters on the basolateral membrane. These influx transporters include organic anion‐transporting polypeptides (OATP), organic anion transporters (OAT), and organic cation transporters (OCT), all of which belong to the solute carrier superfamily. OATP1B1 and OAT1B3 also are involved in bilirubin and bile acid uptake; however, the sodium taurocholate co‐transporting polypeptide (NTCP) is primarily responsible for transporting bile acids into the hepatocyte from the sinusoidal space. The bile salt export pump (BSEP) transports bile salts from the hepatocyte into the biliary canaliculi, while the multidrug resistance‐associated protein 2 (MRP2) transports sulphated bile salts as well as drug metabolites into the biliary canaliculi. Multidrug resistance protein 3 (MDR3) and ATPase Phospholipid Transporting 8B1 (APT8B1) translocate phospholipids that, together with bile acids, form mixed micelles which protect the biliary tree from the detergent‐like effects of bile salts. Located on the basolateral membrane, multidrug resistance associated proteins MRP3 (ABCC3) and MRP4 (ABCC4) return drug metabolites and bile acids to the liver sinusoids. If cholestatic conditions exist, MRP3 and MRP4 are upregulated to protect hepatocytes from toxic bile acid accumulation. Drug metabolites are exported into the biliary canaliculi by multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein 1 (MATE1), and multidrug resistance‐associated protein 2 (MRP2). ATP8B1, ATPase Phospholipid Transporting 8B1; BCRP, breast cancer resistance protein (BCRP); BSEP, bile salt export pump; MATE, multidrug and toxin extrusion protein; MDR, multidrug resistance protein; MRP, multidrug resistance‐associated protein; NTCP, sodium taurocholate co‐transporting polypeptide; OAT, organic anion transporter; OATP, organic anion‐transporting polypeptide; OCT, organic cation transporter.

Efflux transporters are located either on the basolateral membrane or the canalicular membrane and belong to the ATP‐binding cassette (ABC) transporter superfamily. Multidrug resistance‐associated proteins MRP3 (ABCC3) and MRP4 (ABCC4) are located on the basolateral membrane and return drug metabolites and bile acids from liver cells to the sinusoid blood. Under cholestatic conditions, MRP3 and MRP4 are upregulated in order to protect hepatocytes from bile acid accumulation [28, 29].

Transporters on the canalicular membrane are responsible for the export of drug metabolites and bile components. Drug metabolites are exported into the biliary canaliculi by multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein 1 (MATE1) and multidrug resistance‐associated protein 2 (MRP2). In addition to drug metabolites, MRP2 also transports sulphated bile salts and conjugated bilirubin into the biliary canaliculi. The BSEP transports bile salts from the hepatocyte into the biliary canaliculi. Multidrug resistance protein 3 (MDR3) and ATPase Phospholipid Transporting 8B1 (APT8B1) translocate phospholipids that, together with bile acids, form mixed micelles which protect the biliary tree from the detergent‐like effects of bile salts.

Efficient export of bile salts and acids is essential, as their accumulation can be toxic for hepatocytes due to their detergent‐like effects. Drug interactions or genetic defects that impair hepatic transporters involved in bile salt or phospholipid secretion can result in intrahepatic cholestasis (Table 2.1). For example, mutations in ABCB3, which encodes the phospholipid transporter MDR3, can cause progressive familial intrahepatic cholestasis 3, a condition that usually presents as cholestasis in early childhood and may progress to end‐stage liver disease [31]. MDR3 is inhibited by azole antifungals, including ketoconazole, itraconazole, and posaconazole [33]. Loss‐of‐function mutations in ABCB11, the gene encoding the BSEP, cause progressive familial intrahepatic cholestasis 2 [31] and drugs that inhibit the BSEP, such as bosentan, cyclosporin A, and troglitazone, can induce cholestatic DILI [34, 35].

Table 2.1 Genetic diseases related to hepatic transporters.

Gene/protein	Function	Related disease	Clinical phenotypes	References
Basolateral influx transporters
SLCO1B1 organic‐anion transporting polypeptide 1B1 (OAT1B1)	Sodium‐independent uptake of drugs and endogenous compounds, including bilirubin, bile acids, and statins	Rotor syndrome, caused by deficiency in both OATP1B1 and OATP1B3	Conjugated hyperbilirubinemia, coproporphyrinuria	[27]
SLCO1B3 Organic‐anion transporting polypeptide 1B3 (OATP1B3)
SLC10A1 sodium taurocholate co‐transporting polypeptide (NTCP)	Sodium‐dependent bile acid uptake transporter. Also transports statins	NTCP deficiency	Extreme elevated levels of bile salts	[30]
Canalicular efflux transporters
ATP8B1 ATPase phospholipid transporting 8B1	ATP‐dependent translocation of aminophospholipids into bile lumen	Progressive familial intrahepatic cholestasis 1	Cholestasis in children	[31]
ABCB4 multidrug resistance protein 3 (MDR3)	ATP‐dependent translocation of phosphatidylcholine into bile lumen	Progressive familial intrahepatic cholestasis 3	Cholestasis in children	[31]
ABCB11 bile salt export pump (BSEP)	ATP‐dependent bile acid transport into bile lumen	Progressive familial intrahepatic cholestasis 2	Cholestasis in children	[31]
ABCC2 MRP2: multidrug resistance associated protein 2	ATP‐dependent transport bilirubin and drug metabolites transport into bile lumen	Dubin–Johnson syndrome	Conjugated hyperbilirubinemia, jaundice	[32]

Increasing evidence has shown that in vitro inhibition of the BSEP is one of the essential mechanisms leading to DILI and is also a recognized risk factor for DILI [34, 36]. However, it has been suggested that BSEP inhibition alone might not be a good predictor of DILI risk [37] as drugs inhibiting the BSEP often inhibit other transporters as well, and it may be the cumulative effect that causes toxic bile acid accumulation [38]. In support of this theory, hepatoxicity induced by isoniazid and rifampicin may be due to the inhibition of both NTCP and BSEP [39]. Additionally, the discontinued HER2 tyrosine kinase inhibitor CP‐724,714 inhibits efflux transporters BSEP and MDR1, which contributes to the toxic accumulation of drug and bile acids [40].