Age-related alteration in hepatic disposition of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and pesticides

Abstract

Idiopathic Parkinson's disease may be caused by environmental neurotoxins such as pesticides, however the major risk factor is old age. We postulated that the high incidence of Parkinson's disease in older people is secondary to age-related impairment of the hepatic detoxification of xenobiotics. Previously, we have shown that there are significant differences between the hepatic disposition of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and pesticides. Here, we investigated whether there are age-related differences in the hepatic disposition of MPTP and pesticides, putatively associated with the pathogenesis of Parkinson's disease. We measured the hepatic disposition of paraquat, dichlorodiphenyltrichloroethane (DDT), malathion and MPTP using the multiple indicator dilution technique in the perfused livers of Fischer F344 rats aged 3 and 18 months. The recoveries of MPTP, DDT and malathion were increased from the livers of the older rats (by 258%, 253% and 134% compared with young rats, respectively). The hepatic transport of DDT and malathion into hepatocytes was reduced with age suggesting that part of the impaired uptake of neurotoxins may be secondary to an age-related barrier to influx. Ageing may increase risk of Parkinson's disease by altering hepatic detoxification and increasing systemic bioavailability of neurotoxins.