Risk for K-ras gene mutations in smoking-induced lung cancer is associated with cytochrome P4501A1 and glutathione S-transferase micro1 polymorphisms.

Polycyclic aromatic hydrocarbons (PAHs) and other tobacco-related carcinogens are oxidized by phase I enzymes into reactive metabolites that are then detoxified by phase II enzymes. These findings suggested that polymorphisms in genes controlling metabolism of carcinogens underlie individual variations in cancer susceptibility. Moreover, it is unclear whether there is a relation between genetically determined individual susceptibilities and target gene mutations in lung carcinogenesis.

Identification of domains participating in the substrate specificity and subcellular localization of the multidrug resistance proteins MRP1 and MRP2.

The human multidrug resistance protein MRP1 and its homolog, MRP2, are both thought to be involved in cancer drug resistance and the transport of a wide variety of organic anions, including the cysteinyl leukotriene C4 (LTC4) (Km = 0.1 and 1 microm). To determine which domain of these proteins is associated with substrate specificity and subcellular localization, we constructed various chimeric MRP1/MRP2 molecules and expressed them in polarized mammalian LLC-PK1 cells.

Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome.

Dubin-Johnson syndrome (DJS) is a hereditary disease characterized by hyperbilirubinemia. We investigated the consequences of 2 missense mutations, R768W and Q1382R, of nucleotide-binding domains (NBDs) of the multidrug resistance protein 2 (MRP2; ABCC2) that were previously identified in patients with DJS. Pulse chase analysis revealed that the precursor form of the wild-type and Q1382R MRP2 were converted to the mature form, which is resistant to endoglycosidase H (Endo H) in about 60 minutes.