The ABC Transporters

For the longest time we all worked on the premise that drug molecules moved across the cell membranes passively, and by virtue of their lipophilicity. In technical terms, this was determined by the water:octanol partition coefficient. But increasingly we are seeing that this is not all there is to the story. It would seem that few drug molecules actually traverse the lipid bilayer by passive diffusion. Few would cross the membrane without engaging the transport process in some way or other.

One important and very fundamental part of this process is mediated by a superfamily of drug transporters called the ABC transporters. The 'ABC' stands for ATP-Binding Cassette. Apart from having at least one ATP-binding domain, these transporters are characterized by a signature sequence of amino acid residues within the nucleotide binding domain - an LSGGQ motif.

In contrast to prokaryotes, the ABC transporters function as efflux pumps, which together with the detoxification enzymes constitute a complex integrated 'chemo-immunological defense' system against drugs and other xenobiotics.

In human beings, this superfamily of transporters comprises 48 members grouped into 7 families. Just how fundamental these transporters is evidenced by the ubiquity in all living systems be they eukaryotes or prokaryotes. Even mitochondria carry at least 4 of their own ABC transporters.

Prokaryotes
Agrobacterium tumefaciens - 135
Fungi/yeast
Saccharomyces cerevisiae - 22
Plasmodium - 15
Mitochondria - 4
Human - 48

The ABC transporters and their SLC (solute carrier) counterparts are fast shaping up to be probably the most important determinants of interindividual differences in drug efficacy/toxicity.

31st Pharmacological and Therapeutic Society of Thailand Meeting

I just spent 3 wonderful days in Khon Kaen, Thailand at the 31st Pharmacological and Therapeutic Society of Thailand Meeting. I was there as the honoured guest of the Society to deliver the 'Chiravat Sadavongvivad Memorial Lecture was on " The ABC Transporters: Their role in determining drug resistance and drug response'. The proceedings are published in the Thai Journal of Pharmacology. For Khon Kaen University, see here.

Apart from enjoying the characteristically warm and wonderful hospitality of the hosts, it was a great time to catch up with old friendships and also on an academic front, to try and understand a bit more about Thai ideas of ethnicity issues.

ABCC11 Transporter

The ABCC11 gene encodes for a little known member of the ABC (ATP binding cassette) superfamily of membrane transporters. The protein is called MRP8 or multi-drug resistance protein 8. Not much is yet known about its function. It became 'famous' largely because of its association with the dry-wet ear wax phenotype. Additionally, it has been shown to transport cyclic nucleotides e.g. cAMP and cGMP, and consequently has been implicated in resistance to a number of nucleotidic anticancer drugs used for breast cancers.

Other interesting associations other than ear wax....is the association with the production of colustrum by nursing mothers (early milk).

The main genetic polymorphism associated with ABCC11 is the 538G-A transition in exon 4 giving rise to a substitution of glycine to arginine. The frequency of this polymorphism is unknown among our local ethnic groups is Singapore.

What's with the Japanese - wet or dry ear wax??

Another interesting bit of trivia I discovered when I visited RIKEN. There is a genetic polymorphism affecting the ABC (ATP-Binding Cassette) transporter ABC11, that determines if your ear wax comes out dry or wet. This was discovered by Yoshiura et al in 2006. See also report in the New York Times. Apparently the Japanese and Koreans (and Northern Chinese) exclusively have the 'dry ear wax' variant while African and West Europeans have the "wet ear wax" phenotype. The rest of the world have mixed proportions of dry and wet waxes. In Southern China and South East Asia, the frequency of wet wax increases. It is thought that the dry wax allele originated in Northern Asia, thus giving rise to an exclusive distribution of the allele in North China, Korea and Japan.

Wet is black, dry is white

The Japanese use the dry wax phenotype to distinguish the Yamato Japanese from the other Japanese arising from Hokkaido (Ainus) and Ryukyu (Okinawans).

Why not take the ear wax poll?