*6.4. Other Disease Conditions in Connection with ABCG2 Variants*

Abcg2-deficent mice showed no signs of any noticeable phenotype until they were exposed to light, which in turn induced severe phototoxic lesions on the skin of the animals [67]. This led to the discovery that pheophorbide A, the breakdown product of chlorophyll, is an ABCG2 substrate, and the transporter restricts the intestinal uptake of this potential toxic compound. The level of the heme precursor protoporphyrin IX was also massively increased in the RBCs of Abcg2 knockout mice, implying a role for ABCG2 in heme homeostasis. This was further supported by the observations that ABCG2 is upregulated during erythroid differentiation and lowers the PPIX levels in erythroid cells [50]. A comprehensive in vitro study demonstrated that numerous ABCG2 polymorphisms, such as Q126X, F208S, S248P, E334X, S441N, and F489L, cause abrogated porphyrin transport regarding specific (normalized) activities [113]. It should, however, be noted that among these mutants, the expression level of the Class 1 variants (Q126X, F208S, and E334X) was practically zero, and thus no transport activity is expected anyway. These data and the observations with the Abcg2 knockout mice implicate a role for ABCG2 variants in erythropoietic protoporphyria (EPP), a disease of the heme biosynthesis pathway. EEP is caused by either genetic determinant (mutations in the heme biosynthesis enzymes), or by exposures to toxins or drugs, such as rifampicin and isoniazid. Accumulation of PPIX in EPP patients causes hepatotoxicity and phototoxicity primarily in the skin. A recent study elegantly demonstrated that Abcg2-deficency prevents mice from EPP-associated phototoxicity and hepatotoxicity by altering the disposition of PPIX [68]. In this case, this phototoxin is mostly retained in the RBCs, thus causing a reduced plasma level and preventing PPIX accumulation in the skin and the liver/bile. This surprising result clearly elucidates the multifunctionality of ABCG2: on one hand, it restricts the intestinal absorption of the xenobiotic phototoxin pheophorbide A, preventing light-induced skin damage; on the other hand, it facilitates release of the endogenous phototoxin PPIX from RBCs, contributing to the toxic effects, when PPIX is

in excess (e.g., in EPP patients). Seeing pharmacogenomic or human in vivo data in connection with ABCG2 genotypes and ECC would be rather intriguing.

Several ABC transporters, including ABCA1, MDR1/ABCB1, MRP1/ABCC1, ABCG2, and ABCG4, have been implicated in the pathogenesis of Alzheimer's disease (AD) [197,198], a progressive neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides in the brain. Both in vitro and in vivo data demonstrated an ABCG2-dependent efflux of Aβ1-40, suggesting that ABCG2 at the blood-brain barrier prevents Aβ peptide from entering the brain [198,199]. In addition, an upregulation of ABCG2 has been found in the brains of AD patients with cerebral amyloid angiopathy [199], which was also reflected by increased ABCG2 expression levels observed in the RBCs of late-onset AD patients [69]. The role of ABCG2 in AD can be modulated by the mutations/polymorphisms. A lower prevalence of the Q141K was seen in late-onset AD patients, and interestingly increased susceptibility to AD was associated with the Q141K allele containing genotypes.

Besides AD, another neurodegenerative disorder, Parkinson's disease (PD), has also been linked to ABCG2. Previously, higher levels of the natural antioxidant urate in the serum or the cerebrospinal fluid were associated with the clinical decline of PD patients [200,201]. Accordingly, the Q141K polymorphism was correlated with later disease onset of PD [202]; however, a recent study did not find association of the Q141K allele (or the high plasma level of urate) with the disease [203].

Intrauterine growth restriction (IUGR) is one of the most common forms of pregnancy complications. The idiopathic form of IUGR has also been linked to ABCG2, which is abundantly expressed in the placenta. Markedly decreased ABCG2 expression levels were found in placentas from IUGR pregnancies [204]. Based on this observation and the fact that trophoblasts in IUGR are subjected to excessive oxidative stress and apoptotic signals, a role for ABCG2 has been proposed in the protection of trophoblasts against stress-induced apoptosis, although the actual underlying mechanism is yet to be elucidated.

Recently, it has been reported that the expression level of ABCG2 is reduced in the RBC membranes of patients with type 2 diabetes and carrying the Q141K polymorphism, whereas this difference was not observed in patients homozygous for the wt ABCG2 [205]. The mechanism here too is yet to be clarified, but this observation clearly indicates the differential regulation of the wt and the Q141K polymorphic ABCG2 variants.

The actual role of ABCG2 in various stem cell types is still elusive, but it has become commonly accepted that ABCG2 has a protective role in stem cells, as they are exceptionally sensitive to environmental stresses [42,47,148,206]. The high-level expression of ABCG2 in pluripotent stem cells rapidly declines during differentiation [43], but may also regain in differentiated progeny cells that typically express ABCG2, e.g., in hepatocytes [207,208]. In addition to cell differentiation, various environmental impacts can elicit a drop in ABCG2 expression [43,44]. Not only its overall expression, but also its localization can be altered in response to stresses, e.g., mild oxidative stress evokes a reversible internalization of the transporter in pluripotent stem cells [209]. Nevertheless, little is known about the impact of various mutations/polymorphism in ABCG2 on its role in stem cell defense mechanisms. Exceptional medical relevance has the ABCG2 expression in cancer stem cells or drug-tolerant persisters, which can rapidly adapt to chemotherapy and repopulate the tumor [45–48,210]. The presence of these cell subpopulations in the tumors is an increasingly acknowledged reason for chemotherapy failures.
