What is the role of the P-glycoprotein pump and the Multi Drug Resistant 1 (MDR1) gene?
Cells are like little cities and have methods of removing waste and toxic materials. One removal method is a protein pump that sits on the cell membrane and pumps materials out. This is called P-glycoprotein, which means it contains both sugars (glyco) and proteins. A gene codes for the P-glycoprotein pump, and some dogs inherit a healthy gene; others, a gene that has mutated. The mutated gene, the Multi Drug Resistant 1 (MDR1) gene, codes for a defective P-glycoprotein that cannot pump drugs from the cell. Thus, drugs accumulate and have a toxic effect even when given at normal doses.
Dogs inherit genes from both their sire and dam so that they can have one defective gene or they can have two defective genes. Dogs with one defective gene (heterozygous for the defect) have less severe symptoms than dogs with two defective genes (homozygous for the defect).
What Role Do Cell Enzymes (CYP3A) Play?
In addition to having proteins on the membrane that remove drugs from the cell, most cells have enzymes that break down drugs and inactivate them. Cytochrome P 450 (CYP 450) is a family of enzymes that inactivates about 60% of drugs used in pets. One of the CYP 450 family—CYP3A—can be blocked or inactivated by ketoconazole and by grapefruit juice. With CYP3A inactivated, drugs reach toxic concentrations within cells.
Dogs can have both the defective MDR1 gene and have inactivated CYP3A enzymes. These dogs are very likely to develop toxicity with certain drugs.
Which Herding-Breed Dogs Have the MDR1 Gene?
- Australian Shepherd
- Australian Shepherd Mini
- Border Collie
- English Shepherd
- German Shepherd
- Old English Sheepdog
- Shetland Sheepdog
- Mix breeds with any of the above
Two sighthound breeds have the MDR1 gene:
- Longhaired Whippet
- Silken Windhound
Which Drugs Become Toxic If Not Pumped Out by P-glycoproteins?
Many different drugs are normally pumped from cells by P-glycoproteins: anticancer drugs, antiparasitics, antibiotics, cardiac drugs, immunosuppressants, opioids, steroid hormones, and miscellaneous drugs. The following is an alphabetical list of some of the drugs that can become toxic in dogs with the MDR1 mutation:
- Actinomycin D
Which Drugs Inactivate Normal P-glycoprotein Pumps?
Some dogs have normal P-glycoprotein pumps (they don't have the MDR1 mutation), but their P-glycoprotein pumps are inactivated by certain antidepressants, antibiotics, cardiac drugs, immunosuppressants, opioids, and miscellaneous pharmaceuticals. When the pumps are inactivated, dogs experience toxic overdoses of drugs normally cleared by the pump. The following items inactivate normal P-glycoprotein pumps:
- Grapefruit juice
- Saint John's Wort
Any dog—whether with normal P-glycoproteins or abnormal P-glycoproteins—is at risk for developing drug toxicity when taking the above items in conjunction with medications normally cleared by P-glycoproteins.
What Happens When Dogs with the MDR1 Gene Take Drugs They Should Avoid?
The range of symptoms that dogs exhibit when they have the MDR1 gene mutation depends upon the nature of the drug they take. As examples, here are descriptions of symptoms caused by cancer drugs, ivermectin, digoxin, acepromazine, and opoids.
When dogs with cancer in organs that express the MDR1 gene (placenta, brain, kidneys, intestines, gallbladder, and testes) are given the anticancer drug doxorubicin, they have two problems. First, the doxorubicin has no effect on the cancer and the tumor is said to be chemotherapy resistant. Second, the dog develops severe diarrhea, bone marrow suppression, and loss of appetite.
Ivermectin is an antiparasitic. It is used at low doses to kill heartworm microfilaria and at higher doses to treat mange. When herding dogs with MDR1 gene mutation are given Ivermectin to treat mange, they experience central nervous system (CNS) effects: cranial nerve abnormalities, coma, hyper salivation, dilated pupils, loss of balance (ataxia), and poor reflexes.
Digoxin is given to dogs with weak hearts, such as occurs with congestive heart failure. Herding dogs with MDR1 gene mutation develop anorexia, vomiting, and cardiotoxicity if given normal doses of digoxin.
Acepromazine is given to calm dogs, but it puts dogs with MDR1 gene mutation into a stupor.
Opoids (loperamide, butorphanol, and morphine) are given to stop diarrhea (loperamide) and to relieve pain (butorphanol and morphine). When these drugs are given to dogs with MDR1 gene mutation, they become stuporous.
How Can Dogs Get Tested?
The Veterinary Clinical Pharmacology Lab (VCPL) at the College of Veterinary Medicine at Washington State University developed a test that identifies dogs carrying the MDR1 gene. The lab can determine whether a dog has a single abnormal gene or two abnormal genes. Dogs with two abnormal genes (homozygous for the genetic mutation) experience the most severe problems with toxicity if given drugs listed above. When veterinarians have this information, they can decrease the dose if dogs must have any potentially toxic drugs.
To order a test, phone 509-335-3745, or visit the Veterinary Clinical Pharmacology Lab's web site www.vetmed.wsu.edu/vcpl and use the contact information. Instructions for collecting the sample from inside your dog's mouth are on the website. The lab charges $60.00 and completes the test within 3-5 days. Discounts are available if five or more dogs are tested.
Tremendous mental and physical demands are placed on herding dogs. We can avoid causing them any unnecessary problems with toxicity if we understand their potential for sensitivity to certain drugs. Sensitivity is caused by inheriting the Multi Drug Resistant 1 (MDR1) gene, by taking drugs that inactivate normal P-glycoproteins, or by taking substances that inactivate the CYP3A enzyme. With knowledge and support, our herding dogs can stay healthy and reach their full potential.