Is there a single reason why people have adverse events to the Fluoroquinolones?

No… not really. It really all boils down several reasons or a combination of factors. In some individuals we see poor metabolization of the Fluoroquinolone molecule. This is probably due to genetic CYP phenotypes COMBINED with other systemic variables and concomitant substances. Once they metabolize improperly and depending how much of the dosage breaks down into various metabolizes, you are heading for an adverse event.  At that point it depends on the type of metabolites that are left over from the original molecule, quantity of the left over metabolites, and probably systemic variables such as cellular PH, trace elements (metals), and a host of factors.

It would seem that CYP polymorphisms could play a role, in part especially in shotgun reactions or adverse events that come on fairly quickly. Cytochrome P450 (CYPs) are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism. These pathways are highly polymorphic or heterogeneous (variable) in humans, plus there are so many other drugs and naturally occurring compounds that influence  CYP activity as well.  Because of this, trying to quantify their involvement in a Fluoroquinolone adverse event is difficult. 

The Fluoroquinolones also display cumulative toxicity patterns.  Meaning that they have a ‘threshold,’ much like certain anti-cancer chemotherapy.  When this threshold is crossed an adverse event ensues.  Other drugs, such as certain anti-malarials, can contribute to this cumulative toxicity. See the article: Cumulative Toxicity of the Fluoroquinolones. 

Due to the heavy epigenetic quality of the Fluoroquinolones the molecule can metabolize normally and still ‘switch on’ latent genetic predispositions that become pathogenic over time.

Some things that have been ruled out as universally causing floxing are Blood Type, MTHFR, G6PD.*

* These issues could very well play an important role in the severity, type, and length of some symptoms in certain individuals  In other words they could affect downstream issues.