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

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.

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].

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.

For the major CYPs the single nucleotide polymorphism (SNP) has been estimated to be 14–127 per kilobase pair [62]. Of these SNPs, 9–41% are nonsynonymous variants. Only a limited number of SNPs (6–30%) have been cataloged or functionally annotated by the Pharmacogene Variation (PharmVar) Consortium, a public central repository for pharmacogene (PGx) variation ( www.pharmvar.org). In addition to SNPs, variations such as insertions and deletions are present. The polymorphism phenotype can be categorized into four types; i.e. poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra rapid metabolizer. Poor metabolizer usually refers to individuals carrying homozygous or compound heterozygous null alleles (no function). In intermediate metabolizers one allele is partially defective while the other either is partially defective or null. For extensive metabolizers at least one allele is fully functional. Individuals with gain‐of‐function polymorphisms, e.g. carrying extra gene copies and mutations that enhance enzyme activity, belong to the ultra rapid metabolizer category.