Transporters and Drug-Metabolizing Enzymes in Drug Toxicity. Albert P. Li

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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].

2.5 Genetic Variants and Their Impact for Pharmacokinetic Behavior and Safety

Genetic variation can result in decreased, unchanged, or increased enzymatic function [41, 42], and therefore could significantly impact drug safety by altering pharmacokinetic characteristics in certain individuals [43]. Based on decades of pharmacogenetic research, the association between genetic variation and drug metabolism has been established for many drugs [44]. The FDA has published a list of pharmacogenetic associations with sufficient scientific evidence [45]. However, often contradictory evidence for a given drug is reported, usually due to the limited statistical power in many studies. This is of particular importance in establishing associations between genotypes and DILI, as DILI has a very low incidence (~20 per 100 000 inhabitants annually) and clinical diagnosis is challenging [46]. The association between genotype and hepatotoxicity has been suggested for CYP2C9‐Bosentan, NAT2‐isoniazid and others (Table 2.2).

Table 2.2 Selected reports for the association between gene variations and drug‐induced liver injury.

Gene	Variant	Function	Affected subgroups	Drug	DILI risk association	References
CYP2B6	*1H and *1J (‐2320T>C)	Increased expression	Ultrarapid metabolizers	Ticlopidine	Increased risk	[47]
CYP2B6	*6	Decreased function	Poor metabolizers	Efavirenz	Increased risk	[48]
CYP2C9	*2	Decreased function	Poor metabolizers	Bosentan	Increased risk	[49, 50]
CYP2E1	c1/c1	Increased expression	Ultrarapid metabolizers	Isoniazid	Increased risk	[51]
NAT2	*4	Without active alleles	Slow acetylators	Isoniazid	Increased risk	[51–53]
UGT1A6	A528G	Silent mutation		Tolcapone	Increased risk	[54]
UGT2B7	*2	Decreased function	Poor metabolizers	Diclofenac	Increased risk	[55, 56]
GSTM1 and GSTT1	Double null genotype	Decreased function	Poor metabolizers	Troglitazone	Increased risk	[57]
ABCB1	3435C>T	Decreased expression		Nevirapine	Decreased risk	[58, 59]
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