Molecular basis of preferential resistance to colchicine in multidrug-resistant human cells conferred by Gly-185 yields Val-185 substitution in P-glycoprotein

Journal Article · Sat Sep 01 00:00:00 EDT 1990 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.87.18.7225· OSTI ID:5394344

Safa, A R; Stern, R K; Choi, Kyunghee; Agresti, M; Tamai, Ikumi; Mehta, N D; Roninson, I B ^[1]

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1. Univ. of Chicago, IL (USA)

Expression of P-glycoprotein, encoded by the human MDR1 gene, results in cross-resistance to many lipophilic cytotoxic drugs (multidrug resistance). P-glycoprotein is believed to function as an energy-dependent efflux pump that is responsible for decreased drug accumulation in multidrug-resistant cells. Previous work showed that preferential resistance to colchicine in a colchicine-selected multidrug-resistant cell line was caused by spontaneous mutations in the MDR1 gene that resulted in a Gly-185 {yields} Val-185 substitution in P-glycoprotein. The authors have now compared transfectant cell lines expressing the wild-type Gly-185 or the mutant Val-185 P-glycoprotein with regard to their levels of resistance to and accumulation and binding of different drugs. In cells expressing the mutant protein, increased resistance to colchicine and decreased resistance to vinblastine correlated with a decreased accumulation of colchicine and increased accumulation of vinblastine. Expression of the mutant P-glycoprotein also resulted in significantly increased resistance to epipodophyllotoxin and decreased resistance to vincristine and actinomycin D; smaller changes in resistance were observed for several other drugs. Unexpectedly, the mutant P-glycoprotein showed increased binding of photoactive analogs of vinblastine and verapamil and the photoactive compound azidopine and decreased binding of a photoactive colchicine analog. These results suggest that the Gly-185 {yields} Val-185 substitution affects not the initial drug-binding site of P-glycoprotein but another site, associated with the release of P-glycoprotein-bound drugs to the outside of the cell.

• OSTI ID: 5394344
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 87:18; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ACTINOMYCIN
ALKALI METAL COMPOUNDS
ALKALOIDS
AMINO ACIDS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTIBODIES
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
ANTIPYRETICS
AROMATICS
BETA DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
CARBOXYLIC ACIDS
CELL CULTURES
CENTRAL NERVOUS SYSTEM DEPRESSANTS
COLCHICINE
DAYS LIVING RADIOISOTOPES
DOXORUBICIN
DRUGS
DYES
ELECTRON CAPTURE RADIOISOTOPES
FLUORESCEIN
GENE REGULATION
GENES
GLYCINE
GLYCOPROTEINS
HALIDES
HALOGEN COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY ACIDS
HYDROXY COMPOUNDS
INORGANIC PHOSPHORS
INTERMEDIATE MASS NUCLEI
INTERNAL CONVERSION RADIOISOTOPES
IODIDES
IODINE 125
IODINE COMPOUNDS
IODINE ISOTOPES
ISOTOPES
KINETICS
MAMMALS
MAN
MEMBRANE PROTEINS
MEMBRANE TRANSPORT
MONOCLONAL ANTIBODIES
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
PHENOLS
PHOSPHORS
POLYPHENOLS
PRIMATES
PROTEINS
RADIOISOTOPES
REACTION KINETICS
SODIUM COMPOUNDS
SODIUM IODIDES
TRITIUM COMPOUNDS
UPTAKE
VALINE
VERTEBRATES