Year: 2014
Type: article
Abstract: Pharmacogenomics is the study of how genes affect a individual response to drugs to develop medications tailored to a person’s genetic makeup because the efficacy/safety profile have not be the same way for everyone. Mitochondria are characterized by a unique milieu, with an alkaline and negatively charged interior (pH value 8) due to the proton pumping associated with OXPHOS and a series of specific channels and carrier proteins. As a consequence, mitochondria can easily accumulate lipophilic compounds of cationic character and weak acids in their anionic form, particularly amphiphilic xenobiotics including ethidium bromide, 1-methyl-4 phenylpyridinium (MPP+), paraquat (1,1’-dimethyl-4,4’-bipyridinium dichloride; PQ) and others that can penetrate the inner mitochondrial membrane (IMM) freely since in their undissociated forms. Indeed, it is well understood that many drugs and chemicals can cause mitochondrial dysfunction (mitotoxicity) by interacting with mitochondrial DNA (mtDNA), protein synthesis, respiratory chain, other metabolic processes, channels and transporters Moreover, due to its peculiar uniparental maternal inheritance and high mutation rate, mtDNA presents different clusters of population-specific-polymorphism (SNPs) that characterize different maternal lineages (mitochondrial haplogroups). It has been demonstrated that many non-synonymous SNPs, cause amino acid variations in the mitochondrial-encoded proteins, potentially modifying OXPHOS activity and ROS production. Some of these haplotypes may confer vulnerability to, or protection from, various common diseases. Well-documented examples are the role of mtDNA haplotype in Parkinson’s disease (PD) and Leber’s hereditary optic neuropathy (LHON). It has been proposed that European haplogroups J and K are protective for PD. On the other hand the haplogroups J and T may influence mitochondrial dysfunction, resulting in an increased risk of PD. In addition the 11778/ND4, 14484/ND6 and 3460/ND1 LHON mutations are associated respectively with mitochondrial subhaplogroup J2b, J1c and K, as these mtDNA backgrounds may increase penetrance of LHON mutations. Several reports suggest that environmental factors such as pesticides (e.g. rotenone), herbicides (e.g. paraquat) and MPTP or 1-methyl 4-phenyl 1,2,3,6-tetrahydro-pyridine (contaminant in the illicit synthesis of opiates) increase the risk of PD due to a reduction in ATP synthesis and increase of reactive oxygen species (ROS). Furthermore, tobacco smoking has been proposed as an environmental trigger of visual loss in LHON, due to the presence of substances, contained in the tobacco that can directly act inhibiting CI. Researchers have also associated non synonymous variants in mtDNA with the development of side effects of drugs. Effectively the analysis of mtDNA haplogroup in patients with cancer treated with chemioterapic agent cisplatin (cisPt) revealed an increased incidence of hearing loss in haplogroup J, due to inhibition of mtDNA replication. It has also been shown that patients treated with the antibiotic Linezolid may develop LHON-like optic neuropathy, myelosuppression and lactic acidosis. This is possibly due to the inhibition of mitochondrial protein synthesis, which is modulated by the SNPs at positions 2706 and 3010, in the 16S gene of mtDNA. This sequence region is predicted to be very close to the Peptidyl Transferase Center (PTC) that is the binding site of several antibiotics. To demonstrate that mitochondrial genetic variability may influence individual susceptibility to drugs toxicity (Linezolid and CisPt) or to toxic environmental factors (rotenone, MPP+, paraquat and cigarette smoking) we assessed in vitro cell viability, mitochondrial functions including ATP synthesis, activity of OXPHOS complexes and ROS generation, and biogenesis (mtDNA copy number) in a collection of transmitochondrial cytoplasmic hybrids (cybrids) carrying divergent human mtDNA haplogroups (N1b, H, J, T, U, and K) or LHON mutations, that have been defined by sequencing of D-loop region and then of the entire mtDNA. Cybrids were constructed from fibroblasts obtained, after informed consent, from skin biopsies of unrelated healthy subjects and LHON patients. The results of this study demonstrated that mitochondrial genetic variability may influence individual susceptibility to drugs or environmental factors toxicity, highlighting interesting associations between specific haplogroups, mitochondrial functional alterations, and toxic agent. More in details: 1) haplogroup K1 was found to play a protective role against rotenone toxicity, whereas haplogroup J1 seem to be more susceptible to the action of both rotenone and MPP+; 2) haplogroup T seems to be more susceptible to the action of paraquat; 3) haplogroups H12 and T1 in association with the LHON mutation 3460/ND1, and haplogroups J1c and J2A all increase the susceptibility to mitochondrial damage after smoke exposure. Moreover haplogroup H1, characterized by SNPs 2706A/3010A in 16SrRNA is the most sensitive to Linezolid toxicity and haplogroup J appears to act as risk factor in CisPt toxicity. Even though future studies will be necessary to better understand the mechanism of action of some of these molecules, studying the association between mitochondrial haplogroup and toxicity of drugs and chemicals is extremely useful to prevent toxicity in predisposed subjects. This may avoid the occurrence of adverse reactions leading to the withdrawal of drugs from the market or Black Box warnings by FDA. For these reasons, pharmaceutical companies have introduced early in the drug-development process stringent in vitro studies to evaluate mitochondrial function (respiratory chain, ROS, membrane potential and mtDNA).
Author: Daniela Strobbe
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W157655888