Tox and Hound – The Secret Life of Vacor

by Sarah Shafer

Vacor was the scourge of rats everywhere in the United States until 1979, when it was removed from the marketplace after we realized that it was not just deadly to rats, but also to humans. It smelled like peanuts, which may have been the reason that it appealed to kids and people with an appetite for rat poison. Vacor is one of my favorite poisons because it’s elegant, precise, and leads to a miserable death for a rat that’s resistant to coumadin-based poisons.

Vacor entered the market in 1975 as a “safe” rodenticide. While Vacor is the brand name, its chemical name is N-3 pyridylmethyl-N’ 4 nitrophenyl urea. It also goes by the names PNU, Pyriminil, Pyrinuron, RH-787, and DLP-787. After it came onto the market, there were multiple reports of patients ingesting Vacor and presenting to the hospital with hyperglycemia, ketoacidosis, orthostatic hypotension, and other symptoms of autonomic neuropathy.^​1,2​ Some patients presented with hypoglycemia and seizures before developing the more typical presentation of hyperglycemia.^​3​ Even after stabilization, they were left with brittle, insulin-dependent diabetes and symptoms of dysautonomia causing orthostatic hypotension so bad, that some patients required treatment with ergots just to be able to stand up without losing consciousness.^​2,4​

So, how does Vacor cause diabetes? Beta-islet cells are specialized cells within the pancreas that make and excrete insulin. Without insulin, the cells of our body cannot absorb glucose and starve despite plenty of sugar circulating in the bloodstream. When patients first presented with hyperglycemia and ketoacidosis after Vacor exposure, it was unclear whether the effect was more like type I diabetes in that the body was no longer producing insulin, or if it was more like type II diabetes, where the body was now resistant to the effects of insulin. Researchers quickly identified that Vacor actually caused a targeted destruction of beta-islet cells, destroying the body’s ability to produce insulin.^​5,6​ After hundreds of reports documenting human toxicity, Vacor was removed from the commercial market in 1979. However, researchers continue to use Vacor in the lab setting to induce type I diabetes.

Although it was known to cause diabetes, we were never sure about the details of how Vacor worked. We’ve suspected that it works by interfering with nicotinamide metabolism for a while now, and more specifically, by working as a nicotinamide agonist. Part of the reason for this is that nicotinamide, if given within the first three hours of exposure, is a really effective antidote for Vacor poisoning. Nicotinamide is a variant of vitamin B3 (niacin), or nicotinic acid. It is involved in the production of nicotinamide adenine dinucleotide (NAD), which is an important cofactor in numerous biochemical reactions. NAD carries electrons for reactions that require electron transport. It is kind of like a biochemical battery that is used to fuel reactions. Without NAD, our bodies would cease to function in a matter of seconds to minutes. NAD is vitally important, so if Vacor interferes with nicotinamide, therefore interfering with NAD production, why does Vacor target beta-islet cells so specifically?

Turns out the answer may lie with the enzymes used to produce NAD. The body produces NAD in various ways. One major pathway involves a two-step process converting nicotinamide into NAD. The first enzyme in this pathway, nicotinamide phosphoribosyltransferase (NAMPT), is the rate-limiting step of the process.^​7​ The second enzyme, nicotinamide nucleotide adenylyltransferase (NMNAT), changes nicotinamide mononucleotide (NMN) to NAD. Because of the importance of NAD synthesis there are some redundant systems. So, even if NAMPT is blocked, there are other pathways available that can change nicotinamide to NMN. However, there are no such redundant systems if NMNAT is blocked. If this enzyme is blocked NMN isn’t converted to NAD, and without NAD, biochemical chaos ensues.

In 2018, Buonvicino et al. hoped to develop a new kind of chemotherapeutic that targeted the nicotinamide pathway. Specifically, they wanted to block the second step of NAD synthesis, the one involving NMNAT. What they found was that Vacor enters into the NAD production pathway as a placeholder for nicotinamide, eventually becoming Vacor adenine dinucleotide (VAD). This changeling binds to the same place as nicotinamide on the first enzyme, NAMPT, forming a Vacor-version of NMN called Vacor mononucleotide, or VMN.^​7​ In the normal NAD production pathway, NMN binds NMNAT to produce NAD. However, when Vacor is present, VMN will bind NMNAT instead, forming VAD.^​7​ Once VAD is formed, it interferes with the NAD-dependent reactions of glycolysis to such a severe degree that it triggers cell death.^​7​ Interestingly, NMNAT has a 10-fold preference for NMN as compared to VMN, which explains why giving a high dose of nicotinamide given early after exposure is such an effective antidote.^​7​ By flooding the cell with nicotinamide, it outcompetes Vacor, preventing the formation of VAD, therefore preventing cell death.

So, if Vacor kills cells by interfering with the production of NAD, and NMNAT is the enzyme implicated in this process, why are the effects of the poison so specific? Why isn’t every cell targeted by Vacor? The explanation for this is relatively simple. There are three different forms of NMNAT present in the body: NMNAT1, NMNAT2, and NMNAT3. While Vacor has no effects on NMNAT1, it has some activity at NMNAT3.^​7​ More importantly, it turns out that Vacor is relatively selective for NMNAT2. NMNAT2 is highly expressed in both neurons and pancreatic beta-islet cells, which would explain the symptoms of beta-islet cell destruction and autonomic dysfunction that occur in patients poisoned with Vacor.^​8,9​

The story of Vacor is a real testament to the power of the scientific method. After forty years of carefully recorded observations, we finally understand why this rat poison caused the problems that it did in humans. Its precise destruction is just a reflection of the fact that only a few types of cells express NMNAT2 over the other two types of enzymes. It throws a wrench into finely tuned biochemical processes, causing cells to self-destruct in a pattern that resembles type I diabetes. Uncovering the secrets of Vacor might make it less of a mystery, but it doesn’t do anything to change that fact that it is one of my all-time favorite poisons.