Hmm. These are both very good questions. Firstly, I'll start by saying that I'm not going to claim supremacy on the goings on of the show, but as the GM I'll probably be driving things in whatever direction I think will make for the most enjoyable game. 

1. As for the tone of the show, I think the best comparison (as far as what I was imagining) would be General Hospital meets Buffy the Vampire Slayer. Supernatural is a bit too "monster of the day" (I've only seen the first season so I'm not sure if it changes) with an overarching story. I'm think that a more serial style, progressive plot that keeps to a similar formula would be more conducive to roleplaying.

2. As for the plot. Again, just my original concept (feel free to suggest alterations or improvements) is that the character reincarnate as mythical creatures. They're perfectly human in appearance, but they maintain temperament and powers akin to the creature they reincarnated from. By this point in the show the characters have probably already discovered why they reincarnated and for what purpose (probably gods or demons or some such nonsense masquerading as lawyers or big businessmen), overturned the machinations of whoever the mastermind behind the reincarnation is, and settled into a more easy lifestyle. Now they just keep fighting off the ongoing menace of the god's reincarnated twin cousin while he tries to manipulate them into destroying all the regular humans (again, this is all just off the top of my head). I would imagine that the main characters have enacted their own uneasy Masquerade style system that they enforce and ignore as they please, depending on the maguffin of the arc.